Synthesis of gon-4-enes

ABSTRACT

1. A therapeutic composition having progestational activity comprising as active ingredient a 17-aliphatic carboxylic acid ester of 17α-ethynyl-18-methyl-19-nortestosterone and a pharmaceutical carrier for said compound.

This application is a continuation-in-part of our prior-filed copendingapplication Ser. No. 228,384 filed Oct. 4, 1962, now U.S. Pat. No.3,850,911, issued Nov. 26, 1974, in turn a continuation-in-part of ourpriorfiled copending applications Ser. Nos. 57,904 filed Sept. 23, 1960; 91,341 filed Feb. 24, 1961; 137,535 filed Sept. 12, 1961; 195,000filed May 15, 1962; and 196,557 filed May 16, 1962, all now abandoned.

This invention relates to compositions of matter classified in the artof chemistry as substituted unsaturated gonane derivatives, and toprocesses for making and using such compositions.

The invention sought to be patented in principal composition aspect isdescribed as residing in the concept of a gon-4-ene nucleus havingattached thereto in the 13-position a monovalent polycarbonalkylradical.

The tangible embodiments of the composition aspect of the inventionpossess the inherent general physical properties of being whitecrystalline solids, are substantially insoluble in water and aregenerally soluble in polar solvents such as dimethylacetamide.Examination of compounds produced according to the hereinafter describedprocess reveals, upon ultraviolet and infrared spectrographic analysis,spectral data supporting the molecular structures herein set forth. Theaforementioned physical characteristics, taken together with the natureof the starting materials and the mode of synthesis, confirm thestructure of the compositions sought to be patented.

The tangible embodiments of the invention possess the inherent applieduse characteristics of exerting qualitatively varying hormonal effectsin animals as evidenced by pharmacological evaluation according tostandard test procedures. Such tangible embodiments show androgenic,anti-estrogenic, progestational, blood lipid effects, and anabolicactions, salt retention, salt excretion and central nervous systemeffects. This finding indicates their usefulness in the treatment ofamenorrhea, dysmenorrhea, ovulation block and contraception, functionaluterine bleeding, arteriosclerosis, hormone dependent tumors,infertility, pregnancy maintenance, habitual abortion, weight gain andnitrogen retention, growth stimulation, post operative recovery, healingof wounds, and healing of burns. In particular, it has been establishedthat alterations of the natural steroid structure made possible by ourdiscovery result not merely in a change of degree of hormonal activity,but, as a result of the separation of types of hormonal activity, alterin an unexpected way its basic nature so that a desirable hormone effectis maximized and an undesirable hormone effect is minimized.Furthermore, said tangible embodiments possess the use characteristic ofbeing intermediates for the preparation of composition exerting hormonaleffects as evidenced by standard test procedures.

The invention sought to be patented in a sub-generic composition aspectis described as residing in the concept of a13,17-dialkyl-17-hydroxygon-4-en-3-one (FIG. 1, XV), of which a specificembodiment, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is hereinafterdescribed.

The tangible embodiments of said sub-generic composition aspect possessthe use characteristic of varying hormone effects in animals asevidenced by pharmacological evaluation by standard test procedures. Inclinical tests, said specific embodiment has demonstrated high anabolicpotency and unexpected separation of anabolic and androgenic activities.

The invention sought to be patented in a second sub-generic compositionaspect is described as residing in the concept of a13-alkyl-17-alkynyl-17-hydroxygon-4-en-3-one (FIG. 4, XX), of which aspecific embodiment wherein the alkyl group is 13β-ethyl and the alkynylgroup is 17α-ethynyl is hereinafter described.

The tangible embodiments of said second sub-generic composition aspectpossess the use characteristic of varying hormone effects in animals, asevidenced by pharmacological evaluation by standard test procedures, andin particular have demonstrated a high progestational activity, coupledwith an unexpected separation of activities.

The invention sought to be patented in a third sub-generic compositionaspect is described as residing in the concept of a 17 ester of a13-alkyl-17-hydroxygon-4-en-3-one (FIG. 5, XXIII), of which a specificembodiment in which the alkyl group is 13β-ethyl and the ester is thedecanoate ester is hereinafter described.

The tangible embodiments of said third sub-generic composition aspectpossess the use characteristic of varying hormone effects in animals, asevidenced by pharmacological evaluation by standard test procedures, andin particular in certain instances long-acting anabolic effectsaccompanied by unexpected separation of activities.

The invention sought to be patented, in a principal process of makingthe compositions aspect, is described as residing in the concept of thesequence of reactions including: converting a compound having a5-phenyl-pent-1-yne nucleus, ring-unsubstituted in at least one positionortho to the point of chain attachment, by means of a Mannich-typereaction, to its acetylenic amine derivative; hydrating the acetyleniclinkage to form a 3-keto compound; reacting such 3-keto substratecompound with a nucleophilic 2-monovalent alkyl-1,3-dioxocyclopentanocompound under Michael condensation conditions to attach thecyclopentano compound through its 2-position carbon atom to the1-position carbon atom of the 3-keto compound; treating the bicyclictriketone formed in the preceding step with an acidic dehydrating agentthereby to effect a double cyclodehydration to form a1,3,5(10),8,14-pentadehydro-13-alkyl-gonane; selectively saturating the14(15) double bond of said gonane with hydrogen in the presence of acatalyst; thereafter saturating the 8(9) double bond of the compoundresulting from the preceding step; partially reducing the A-ring doublebonds and the 17-carbonyl group to 17-hydroxymethylene; and, thereafterconverting the so-reduced compound to a4-dehydro-13-alkyl-17-hydroxygonane.

The invention sought to be patented in a second process aspect, asillustrated in annexed FIG. 2, is described as residing in the conceptof a reaction comprising hydrolyzing a compound with agona-2,5(10)-diene nucleus, having attached thereto in the 13-position amonovalent polycarbon-alkyl radical (XVI), under strong conditions, i.e.heat, mineral acid, to obtain a compound with a gon-4-en-3-one nucleushaving attached thereto in the 13-position a monovalent polycarbonalkylradical (XVII).

The invention sought to be patented in a third process aspect, asillustrated in annexed FIG. 3, is described as residing in the conceptof a sequence of reactions including: treating a compound with agona-2,5(10)-dien-17-one nucleus having attached thereto in the13-position a monovalent polycarbon-alkyl radical (XVIII) with an alkylGrignard reagent or metal alkyl to obtain a compound with a17α-alkyl-gona-2,5(10)-dien-17-ol nucleus having attached thereto in the13-position a monovalent polycarbon-alkyl radical (XIV), and hydrolyzingsaid product with mineral acid to obtain a compound with a17α-alkyl-17β-hydroxy-gon-4-en-3-one nucleus having attached thereto inthe 13-position a monovalent polycarbon-alkyl radical (XV).

The invention sought to be patented in a fourth process aspect, asillustrated in annexed FIG. 4, is described as residing in the conceptof a sequence of reactions including: treating a compound with agona-2,5(10)-dien-17-one nucleus having attached thereto in the13-position a monovalent polycarbon-alkyl radical (XVI) with anorgano-metallic derivative of a 1-alkyne to obtain the corresponding17α-alkynyl-gona-2,5(10)-dien-17-ol having attached thereto in the13-position a monovalent polycarbon radical (XIX), and hydrolyzing saidproduct with mineral acid to obtain a17α-alkynyl-17β-hydroxygon-4-en-3-one having attached thereto in the13-position a monovalent polycarbon-alkyl radical (XX).

The invention sought to be patented in a fifth process aspect, asillustrated in annexed FIG. 5, is described as residing in the conceptof a sequence of reactions including: treating a compound with agona-2,5(10)-dien-17-ol nucleus having attached thereto in the13-position a monovalent polycarbonalkyl radical (XXI) with mineral acidto obtain a compound with a 17-hydroxygon-4-en-3-one nucleus havingattached thereto in the 13-position a monovalent polycarbon-alkylradical (XXII), and esterifying the hydroxy group to obtain thecorresponding 17-ester (XXIII).

The manner of making the chemical compounds, which are the startingmaterials for use in making the compounds of the invention, and for usein the processes of making of the invention, are illustrated inco-pending application Ser. No. 228,384 filed Oct. 4, 1962.

In describing the invention, reference will be made in the followingspecification to the annexed drawings, wherein:

FIG. 1 illustrates schematically the reaction sequence for preparing a13-alkylgon-4-ene, specifically13β,17α-diethyl-17β-hydroxygon-4-en-3-one.

FIG. 2 illustrates schematically the mineral acid hydrolysis of a13-alkylgona-2,5(10)-diene to a 13-alkylgon-4-ene, specifically13β-ethyl-3-methoxygona-2,5(10)-dien-17-one to13β-ethylgon-4-en-3,17-dione.

FIG. 3 illustrates schematically the reaction sequence for preparing a13,17-dialkylgon-4-en-17-ol from a 13-alkylgona-2,5(10)-dien-17-one,specifically 13β,17α-diethyl-17β-hydroxygon-4-en-3-one from3-methoxy-13β-ethylgona-2,5(10)-dien-17-one.

FIG. 4 illustrates schematically the reaction sequence for preparing a13-alkyl-17-alkynylgon-4-en-17-ol from a13-alkylgona-2,5(10)-dien-17-one, specifically13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one from13β-ethyl-3-methoxygon-2,5(10)-dien-17-one.

FIG. 5 illustrates schematically the reaction sequence for preparing anester of a 13-alkyl-17-hydroxygon-4-ene from a13-alkylgona-2,5(10)-dien-17-ol, specifically the decanoate ester of13β-ethyl-17β-hydroxygon-4-en-3-one from13β-ethyl-3-methoxygona-2,5(10)-dien-17β-ol.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

Referring now to FIG. 1, wherein the compounds are assigned Romannumerals for identification schematically, the sequence of reactionsinvolved in the synthesis of a specific embodiment, namely,13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated.3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide inbenzene after dropwise addition in the cold to form3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II)dissolved in tetrahydrofuran is condensed with sodium acetylide inliquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). CompoundIII is allowed to stand under nitrogen with water, 30% formalin, aceticacid, diethylamine, dioxan, and cuprous chloride at 70° C for about 12hours, whereby there is obtained1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turnhydrated in the presence of a mercury salt and sulfuric acid to form1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) mayeliminate diethylamine on distillation to give the vinyl ketone6-(m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or theketone (VI), or mixtures thereof, is then reacted with2-ethyl-1,3-cyclopentanedione (VII) under Michael condensationconditions, e.g. refluxing in methanolic potassium hydroxide to form2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).

Compound VIII is then cyclodehydrated at the reflux temperature of asolvent, such as benzene, in the presence of a dehydrating acid, such asp-toluene sulfonic acid, to effect simultaneous ring closures to givethe tetracyclic compound13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (IX). The14-unsaturation of Compound IX is then selectively hydrogenated in thepresence of a metal catalyst, such as 2% palladized calcium carbonate,to form 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (X).Ethynylation at the 17-position of Compound X with lithium acetylide indimethylacetamide gives13β-ethyl,17α-ethynyl-3-methoxygona-1,3,5(10),8-tetraen-17.beta.-ol(XI). The ethynyl group of Compound XI is then selectively hydrogenatedto ethyl, as in the presence of a supported palladium catalyst, toproduce 13β,17α-diethyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol (XII),which is then converted to13β,17α-diethyl-3-methoxygona-1,3,5(10)-trien-17β-ol (XIII) by alkalimetal reduction in liquid ammonia, to provide the normal gonaneconfiguration of 9,8-8,14-14,13 exocyclic substituents, namelytrans-anti-trans.

By alkali metal reduction in liquid ammonia in the presence of a protondonor, such as ethanol (Birch reduction), Compound XIII is converted to13β,17α-diethylgona-2,5(10)-dien-17β-ol (XIV). By hydrolysis in thepresence of mineral acid, Compound XIV is then converted to13β,17α-diethyl-17β-hydroxygon-4-en-3-one (XV).

The compound 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, whenadministered to humans, is strongly anabolic as measured by weight gain,and shows virtually no androgenicity at therapeutic dose levels.Consistent effects on appetite stimulation are present and beneficialeffects upon dermatitis and ichthyosis of mongols have been noted.

To form another specific embodiment of this invention, referring to FIG.4, Compound XVI, 13β-ethyl-3-methoxygona-2,5(10)-dien-17-one is treatedwith an alkali metal acetylide in liquid ammonia to convert it to13β-ethyl-17αethynyl-3-methoxygona-2,5(10)-dien-17β-ol (XIX). CompoundXIX is then converted to 13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one(XX).

When administered orally, this compound,13β-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one, demonstrates unexpectedhigh progestational activity accompanied by a separation of undesirablehormone effects found in the natural steroids.

Referring to FIG. 5, a third specific embodiment of the invention,13β-ethyl-17β-hydroxygon-4-en-3-one decanoate ester (XXIII), is formedby esterification of 13β-ethyl-17β-hydroxygon-4-en-3-one (XXII),obtained by mineral acid hydrolysis of13β-ethyl-3-methoxygona-2,5(10)-dien-17β-ol (XXI). Compound XXI isobtained from 13β-ethyl-3-methoxygona-2,5(10)-dien-17-one, by reductionwith a complex metal hydride, or alternatively from Compound X, FIG. 1,13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one, by complex metalhydride reduction to form13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol, and then alkalimetal in liquid ammonia reduction to obtain13β-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol, followed by alkali metalin liquid ammonia reduction in the presence of a proton donor to formthe before-mentioned Compound XXI.

The compound 13β-ethyl-17β-hydroxygon-4-en-3-one decanoate ester (XXIII)is a long acting anabolic agent with unexpected enhancement of anabolicactivity accompanied by a decrease in androgenic activity.

While the hereinbefore described processes produce novel andsteroidal-like compounds which have an unnatural substituent at the13-position, it is apparent that the novel and valuable processes of theinvention offer a unique feasible route to the corresponding naturalsteroids if the nucleophilic compound used in the Michael condensationstep is 2-methyl-1,3-cyclopentanedione.

The aromatic ring of the phenylpropanol (FIG. 1, I) used as the startingmaterial for the preparation of the compositions and initialpreparations of the invention may have one or more substituents,provided, however, at least one position ortho to the position ofpropanol-chain attachment is unsubstituted so that cyclodehydration toform a cyclic structure can eventually be effectuated. To activate suchortho position for said subsequent ring closure, a para-directing group(referring to electrophilic aromatic substitution) such as hydroxy,acyloxy, alkoxy, amino, alkylamino, or acylamino is a necessarysubstituent on the aromatic ring. The group may be present initially ormay be introduced later but before ring closure, either directly, or byconversion from a meta-directing group such as nitro. After thetetracyclic structure has been formed, substituents can be introducedinto the aromatic A-ring which are not limited as above; however, ifsuch substituted compound is to undergo a reduction, the group ispreferably one not sensitive to reduction. After the A-ring has beenreduced, the substituents on said A-ring may be the same as thoseoriginally present, or substituents on said A-ring may be the same asthose originally present, or substituents to which they may beconverted, such as ketonic oxygen, dialkoxy, alkylenedioxy,alkylenethioxy, and alkylenedithio; or groups introducible by knownprocesses, such as halogen or alkyl. For the processes of the inventionand except for the limitations expressed in this specification,variations of the substituents on the A-ring of the fully formedtetracyclic structures, or on the intermediates leading thereto, arefull equivalents of each other.

The carbon atom to which the phenyl group of the starting propanol (I)is attached can be substituted, as, for example, with an alkyl group,such as methyl or ethyl. Moreover, this atom, to which the phenyl groupis attached in Compound I, need not necessarily be carbon. It can be ahetero atom which would not interfere with subsequent catalyticreductions, as, for example, oxygen or nitrogen. This atom will appearin the tetracyclic structures of the invention in the 6-position, and itwill be apparent, may be, in the case of the nitrogen, substituted withhydrogen or an alkyl group.

The 2-carbon atom of the starting phenyl-propanol (I) can also besubstituted, as, for example, with an alkyl group, such as methyl andethyl, and, as such, be unchanged throughout the subsequent synthesis.In the tetracyclic structures of the invention this carbon atom willappear in the 7-position.

For the processes of the invention and except for the limitationsexpressed in this specification, variations of the B-ring on the fullyformed tetracyclic structures, or on the intermediates leading thereto,are full equivalents of each other.

In the Michael reaction step, the 3-keto substrate compound can be a6-phenyl-1-hexen-3-one, or alternatively, a 6-phenyl-3-hexanone havingattached to the 1-position a group which will eliminate with hydrogen toform a 6-phenyl-1-hexen-3-one under Michael conditions. Thus, a 3-ketocompound with a 1-dialkylamino substituent or its quarternary salt, a1-halo substituent or a 1-hydroxy substituent will react with thenucleophilic compound to form the Michael product. The nucleophiliccompound can be a carbocyclic-1,3-dione of varying ring size, as, forexample, a five-membered ring, a six-membered ring, etc., ultimatelyforming a corresponding five-membered, a six-membered, etc., D-ring inthe tetracyclic structure. The 1,3-cyclodione may also contain a heteroatom at positions other than position 2, thereby to provide aheterocyclic D-ring in the tetracyclic structure. Acylic nucleophiliccompounds can be used in conducting the Michael reaction step and theopen-chain of the resulting product thereafter ring-closed to form acyclic D-ring.

For the processes of the invention, and except for the limitationsexpressed in this specification, variations of the D-ring on the fullyformed tetracyclic structure, or on the intermediates leading thereto,are full equivalents of each other.

When the nucleophilic compound is 2-methyl-1,3-cyclopentanedione, theinvention provides a unique total synthesis for natural steroids: thehydrogens at the 8-position, 9-position, and 14-position being β, α, andα, respectively, as in the natural steroids. Thus such valuabletherapeutic substances as 19-nortestosterone are made available fromeasily obtainable and relatively simple and inexpensive startingmaterials.

Moreover, by varying the group at the 2-position of the nucleophilicMichael condensation reactant, the invention provides a way to producecompounds resembling the natural steroids save at the 13-position. Thus,by varying the substituent at the 2-position of the1,3-cyclopentanedione, alkyl groups of varying chain length such as, forexample, ethyl, isopropyl, cetyl, etc., may be introduced to form thegonane correspondingly substituted at the 13-position. Further, gonanesmay be prepared wherein the 13-position is substituted with any organicradical. Thus, but without limiting the generality of the foregoing, anaralkyl, cycloalkylalkyl, or a polycarbon-alkylene bridge bearing ahydroxy-, amino-, or alkylamino- substituent can readily be placed inthe 13-position, and from such compounds other variations of the13-position substituent can be prepared, as haloalkyls fromhydroxyalkyls, or quaternary salts, amides, alkenyls, etc. fromaminoalkyls.

For the processes of the invention and except for the limitationsexpressed in this specification, variations at the 13-position of thefully formed tetracyclic structures or on the intermediates leadingthereto are the full equivalents of the claimed 13-positionpolycarbon-alkyl substituents, having physiological activity of the sametype.

In any of the intermediate structures or in the tetracyclic structuresof the invention having either an aromatic, partially reduced, ortotally reduced A-ring, wherein the 17-position, or positioncorresponding thereto in the gonane nucleus, is carbonyl, the carbonylgroup can be converted to a group such as hydroxymethylene by lithiumaluminum hydride reduction; to acyloxymethylene by esterification of thehydroxymethylene group so formed; to alkoxymethylene by etherificationof the hydroxymethylene group; to alkylhydroxymethylene by addition ofthe appropriate organo-metallic reagent to the carbonyl; or toalkynylhydroxymethylene by addition of the appropriate alkali metalacetylide in a suitable inert solvent; all in the known manners. Thecarbonyl group may also be ketalized or thioketalized by treating withthe appropriate alcohol or glycol in a suitable solvent under acidicconditions, as in the presence of an acid such as sulfuric acid,p-toluene sulfonic acid, or boron trifluoride etherate, with heatingwhere necessary, according to the known art.

The specific reactions involved in the processes of the invention willnow be considered, as follows, reference being made to the drawings fortypifying compounds:

The vinyl ketones (VI) of the invention are prepared by elimination ofdialkylamine from the corresponding dialkylaminoethyl aminoketones (V),obtained by hydration of the acetylenic linkage in an acetylenic amine(IV). The acetylenic amines (IV) can be themselves prepared by a Mannichreaction from the corresponding acetylene (III) with formaldehyde and adialkylamine. The hydration can be carried out, for example, in aqueoussulfuric acid with mercuric sulfate as a catalyst. The correspondingquaternary salts, which may also be used in the subsequent Michaelcondensation, can be obtained by quaternization of the correspondingacetylenic dialkylaminoethyl amine, followed by hydration; or byquaternization of the ketoamine. The vinyl ketones can be prepared fromthese derivatives by the above elimination reaction. Thus the ketoamineor its quaternary salt can be treated with a base for this purpose, forexample, with sodium hydroxide or a sodium alkoxide.

The vinyl ketones (VI) and dialkylamino ketones (V) are condensed with anucleophilic compound under Michael reaction conditions. Thus thecondensation can be carried out by bringing the two reagents together insolution in the presence of a base, for example, pyridine,triethylamine, diethylamine, sodium hydroxide, or sodium methoxide, andheating as required. The nature and amount of base employed in thecondensation reaction will depend upon the particular reagents used.Where the vinyl ketone derivative employed is a keto-amine anddialkylamine is eliminated in the reaction, no added base may berequired. Where the compound is a 2-alkylcyclopentane-1,3-dione (VII),the compound to be condensed with it is preferably a vinyl ketone, andthe dione is used in excess of the molecular equivalent quantity.Suitable solvents are hydrocarbons, such as benzene, and anhydrousalcohols, such as methanol. If the reaction is carried out in benzeneunder refluxing conditions, water formed in the condensation may beazeotroped out of the reaction mixture with a Dean-Stark type trap.

As hereinbefore noted, monocyclodehydration of the C-ring isaccomplished by an internal aldol condensation. The cyclodehydration cantherefore be carried out using conditions generally applicable for analdol condensation, i.e., in the presence of an acid or basic catalystsuch as NaOH, p-toluene sulfonic acid, triethylamine benzoate, aluminumtertiary butoxide, and the like, either at room temperature oraccompanied by heating if necessary. In most instances, we prefer tocarry out the cyclic dehydration at the boiling point of the solvent topermit azeotropic removal of the water formed during the course of thereaction, inasmuch as the aldol reaction is an equilibrium one.Preferred as solvents are the low boiling anhydrous aromatichydrocarbons, such as benzene and xylene. C-ring closure occursregardless of the nature of the substitution on the aromatic ring.

The reduction of the 8(14) unsaturation in the tricyclic compounds iscarried out by catalytic hydrogenation either at room temperature orabove. It is found that when hydrogen and a palladium-on-charcoalcatalyst are used, the hydrogen introduced at the carbon 14-position isprincipally in the configuration trans to the group attached at the13-position. By whatever mechanism the hydrogen at the 8-position isintroduced, it can on treatment with an acid or base take up the moststable configuration, i.e., the position trans to the other newlyintroduced hydrogen, by equilibrating through keto-enol tautomerism withthe adjacent keto group. Thus the second hydrogen atom can be made totake up the β-configuration when the first is α.

The B-ring closure is brought about under acidic conditions. Suitableare strong acids such as sulfuric, hydrochloric, p-toluene sulfonic,etc. in solvents such as benzene, toluene, anhydrous alcohol, etc. Thereaction is generally carried out at room temperature or below sinceheat may promote the formation of an aromatic B-ring. The preferredtreatment is with methanolic hydrochloric acid at room temperature. Ashereinbefore noted, it has been found that the ease of B-ring closure ofthe compounds of the invention to form tetracyclic compounds is affectedby the nature of the substituent present on the preformed aromaticA-ring, and that subsequent cyclization is easier to carry out when thepreformed aromatic A-ring contains a substituent which activates theposition at which cyclization is to occur. Where a compound is to beused directly for B-ring closure, it will in practice be one containingsuch a substituent. Those substituents which cause subsequent B-ringclosure to occur readily are substituents para to the position of ringclosure which are groups that in electrophilic aromatic substitutionactivate an aromatic ring and are predominantly o- and p- directing; forexample, the hydroxy or alkoxy group.

The double cyclodehydration is brought about by dissolving a compoundtypified by Compound VIII in benzene containing a catalytic amount ofp-toluene sulfonic acid and boiling the mixture under a Dean-Stark trapuntil two equivalents of water have been collected, or alternatively, bytreating the same triketone with polyphosphoric acid at room temperatureor slightly above until ring closure is complete.

The selective hydrogenation of the gona-8,14-dienes typified by CompoundIX is carried out by means of 2% palladized calcium carbonate. Ashereinbefore noted, surprisingly, the catalytic hydrogenation results inaddition of hydrogen to the 14-double bond in such a way as to give the"natural" stereochemical configuration; that is, the hydrogen adds at14-trans to the alkyl at 13. Selective reduction of the 14-trans to thealkyl at 13. Selective reduction of the 14-ethylenic linkage is achievedby use of catalyst-solvent combination which shows adequate selectively,and stopping the hydrogenation when the theoretical amount of hydrogenhas reacted. Solvents showing selectivity in this regard are thenonprotonic solvents, that is, hydrocarbons and ethers; benzene,toluene, naphtha, dioxan, dibutyl ether, and diethyl ether are examplesof suitable nonprotonic solvents. On the other hand, protonic solventssuch as acetic acid and ethanol appear to be largely non-selective.

It has been found that a moderately active Raney nickel catalystprovides good selectivity in a suitable solvent. If a Raney nickelcatalyst of low activity is employed, the hydrogenation may be too slowto be useful; on the other hand, a vigorous catalyst shows poorselectivity and some saturation of the 8,9-ethylenic bond may occursimultaneously with the hydrogenation at the 14,15-position.

If desired, other moderately active hydrogenation catalysts may be usedinstead of Raney nickel; for example, palladium on barium sulfate or onan alkaline earth metal carbonate or on charcoal have all been foundsuitable in this selective hydrogenation.

Saturation at the 8- or at the 9(11)-position of the tetracyclicstructures must be stereospecific to obtain the natural type ofexocyclic substituent configuration as noted supra. Such a sufficientlystereospecific reduction can be in general effected by the action of analkali metal (sodium, potassium, or lithium) in liquid ammonia to thenormal steroid configuration hydrogen at the respective carbons.Preferably this type of reduction is carried out in the presence of aprimary or secondary aromatic amine, for instance aniline, p-toluidine,or diphenylamine, as this can improve the yield of the desired product.The reduction can also be carried out in the presence of a more reactiveproton donor; in this instance, the reduction of the ethylenic linkageoccurs with a simultaneous reduction of the aromatic ring to give a1,4-dihydrophenyl group.

The reduction of 9-dehydro compounds can also be effected by catalytichydrogenation, as this has been discovered to be sufficientlystereospecific for production of the desired trans-anti-trans compoundsof normal configuration.

While the tetracyclic compounds in this specification and the appendedexamples are named to describe the configuration corresponding to thatof the natural steroids, it is to be understood that unless otherwiseindicated, the product of each of the given manipulative procedures is aracemic mixture which contains said named compound and its enantiomorph.

Representative formulations embodying specific compositions of thisinvention follow:

A pharmaceutical tablet for use as an oral anabolic agent consists ofthe following ingredients:

                                mg                                                13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                 5                                                 Carboxymethylcellulose (viscosity 400 cps)                                                                15                                                Lactose powder              25                                                Redried corn starch         25                                                Magnesium stearate powder   4                                                 Calcium silicate powder     q.s.                                                                          200                                           

A capsule for use as an oral anabolic agent contains, in encapsulatinggelatin, the following ingredients:

                                mg                                                13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                 5                                                 Finely divided silica lubricant                                                                           5                                                 Magnesium stearate powder   5                                                 Powdered corn starch        113                                               Lactose powder              q.s.                                                                          245                                           

An anabolic agent suspension for oral use consists of the followingingredients per 5 cc:

                                mg                                                13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                 5.0                                               Magnesium aluminum silicate (thickening agent)                                                            37.5                                              Carboxymethylcellulose of low viscosity                                                                   37.5                                              Polyoxyethylene sorbitan monolaurate                                                                      50.0                                              Glycerin                    250.0                                             Sucrose                     2000.0                                            Methyl p-hydroxybenzoate    5.0                                               Propyl p-hydroxybenzoate    1.0                                               Flavor and distilled water  q.s.                                          

An anabolic agent suspension for parenteral use consists of thefollowing ingredients per cc:

                               mg                                                 13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                0.5                                                Benzyl alcohol             10.0                                               Sodium chloride            90.0                                               Polyoxyethylene sorbitan monooleate                                                                      4.0                                                Sodium carboxymethylcellulose                                                                            5.0                                                Water for injection        q.s.                                           

Pediatric drops for use as an anabolic agent consist of the followingingredients per drop (0.05 cc):

                               mg                                                 13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                0.500                                              Magnesium aluminum silicate (thickening agent)                                                           0.375                                              Polyoxyethylene sorbitan monolaurate                                                                     0.500                                              Disodium phosphate heptahydrate                                                                          0.375                                              Citric acid monohydrate    0.060                                              Glycerin                   1.250                                              Methyl p-hydroxybenzoate   0.025                                              Propyl p-hydroxybenzoate   0.005                                              Butyl p-hydroxybenzoate    0.020                                              Distilled water            0.015                                              Sodium saccharin           0.013                                              Sorbitol and flavor        q.s.                                           

A long-acting anabolic agent tablet consists of the followingingredients:

                                mg                                                13β,17α-Diethyl-17β-hydroxygon-4-en-3-one                                                 5                                                 Water-insoluble acid carboxyvinyl polymer                                     of acrylic acid copolymerized with 0.75-2%                                    of polyallyl sucrose (the Carbopol 934 of                                     U.S. Patent 2,909,462)      150                                               Magnesium stearate powder   2                                                 Lactose                     q.s.                                          

A long-acting anabolic agent suspension for parenteral use consists ofthe following ingredients per cc:

                                  mg                                              13β-Ethyl-17β-hydroxygon-4-en-3-one 17-decanoate                                                  0.5                                             Benzyl alcohol                10.0                                            Sodium chloride               90.0                                            Polyoxyethylene sorbitan monooleate                                                                         4.0                                             Sodium carboxymethylcellulose 5.0                                             Water for injection           q.s.                                        

A progestational agent tablet consists of the following ingredients:

                                 mg                                               13β-Ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one                                            5                                                Spray dried lactose          75                                               Methocel (400 cps)           12                                               Powdered stearic acid        6                                                Talc                         2                                            

Pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets, and suppositories. A solid carrier can be one or moresubstances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, ortablet-disintegrating agents: it can also be an encapsulating material.In powders the carrier is a finely divided solid which is in admixturewith the finely divided compound. In the tablets the compound is mixedwith carrier having the necessary binding properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain from 5 to 10 to 99% of the active ingredient.Suitable solid carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methyl cellulose, sodium carboxymethylcellulose, a low melting wax, andcocoa butter. The term "preparation" is intended to include theformulation of the compound with encapsulating material as carrierproviding a capsule in which the compound (with or without othercarriers) is surrounded by carrier, which is thus in association withit. Similarly, cachets are included. Tablets, powders, cachets, andcapsules can be used for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.The compounds are insoluble in water, but can be dissolved inaqueous-organic solvent mixtures that are non-toxic in the amounts used.As an example may be mentioned water-propylene glycol solutions forparenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solutions. Aqueous suspensionsuitable for oral use can be made by dispensing the finely dividedcompound in water with viscous material, natural or synthetic gums,resins, etc., for example, gum arabic, ion-exchange resins,methylcellulose, sodium carboxymethylcellulose and other well-knownsuspending agents.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is sub-divided in unit doses containingappropriate quantities of the compound: the unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, for example, packeted powders of vials or ampules. The unitdosage form can be a capsule, cachet, or tablet itself, or it can be theappropriate number of any of these in packaged form. The quantity ofcompound in a unit dose of preparation may be varied or adjusted from 1mg to 100 mg (generally within the range of 2.5 to 25 mg) according tothe particular application and the potency of the active ingredient.

The claimed compositions having physiological activity can beincorporated into pharmaceutical formulations includingsustained-release agents.

The following examples illustrate the processes and manner of making thecompositions of the invention.

EXAMPLE 1 1-Dimethylamino-6-m-methoxyphenylhex-2-yne

Allow 5 -m-methoxyphenylpent-1-yne (8 g.) to stand for 12 hours at 70° Cunder nitrogen with water (2.5 cc), trioxan (0.5 g), 30% formalin (5.5g), diethylamine (4 g), acetic acid (2.75 g), dioxan (25 cc) and cuprouschloride (0.13 g). Make the cooled solution alkaline with 10% aqueoussodium hydroxide and extract with ether; then extract the ether extractwith 10% hydrochloric acid: wash the acid extract with ether, makealkaline with 10% aqueous sodium hydroxide, extract with ether, and thenwash and dry the ether extract. Distil to obtain1-diethylamino-6-m-methoxyphenylhex-2-yne (10.6 g. 88%), b.p. 130°-131°C/0.1 mm.

C₁₇ H₂₅ N Calculated: C, 78.7%; H, 9.7%. Found: C, 78.9%; H, 9.6%.

To prepare 1-diethylamino-6-m-ethoxyphenyloct-2-yne treat5-m-ethoxyphenylhept-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-m-propoxyphenylhex-2-yne treat5-m-propoxyphenylpent-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-m-pentoxyphenylhex-2-yne treat5-m-pentoxyphenylpent-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-m-cyclopentyloxyphenylhex-2-yne treat5-m-cyclopentyloxyphenylpent-1-yne (ca. 8 g) according to themanipulative procedure described above.

To prepare 1-diethylamino-6-m-propoxyphenylhep-2-yne treat5-m-propoxyphenylhex-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-(3,5-diethoxyphenyl)-hex-2-yne treat5-(3,5-diethoxyphenyl)pent-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-(3-ethoxy-4-propoxyphenyl)-hex-2-yne treat5-(3-ethoxy-4-propoxy)pent-1-yne (ca 8 g) according to the manipulativeprocedure described above.

To prepare 1-diethylamino-6-(3-ethoxy-4-propoxyphenyl)-hept-2-yne treat5-(3-ethoxy-4-propoxy)-hex-1-yne (ca. 8 g) according to the manipulativeprocedure described above.

EXAMPLE 2 1-Diethylamino-6-phenylhex-2-yne

Maintain 5-phenylpent-1-yne (20 g) for 12 hours at 70° under nitrogenwith water (6.2 cc), trioxan (1.2 g), 30% formalin (13.8 g),diethylamine (10 g), acetic acid (6.9 g), dioxan (62 cc) and cuprouschloride (0.35 g). Make the cooled solution alkaline with sodiumhydroxide. Extract with ether and extract the ether extract itself withhydrochloric acid. Make the purified aqueous hydrochloride solution thusobtained alkaline again and extract with ether. Dry, evaporate the etherextract and distil the residue to obtain1-diethylamino-6-phenylhex-2-yne (27.1 g), b.p. 104°-106°/0.2 mm.

C₁₆ H₂₃ N Calculated: C, 83.8%; H, 10.1%. Found: C, 83.9%; H, 10.1%.

Prepare 1-diethylamino-6-m-nitrophenylhex-2-yne (1.5 g), b.p. 148°C/0.05mm, by treating 5-m-nitrophenylpent-1-yne (1.8 g) with water (0.6 cc),trioxan (0.1 g), 30% formalin (1.4 g), diethylamine (1g), acetic acid(0.7 g), dioxan (6.2 cc) and cuprous chloride (0.03 g) according to themanipulative procedure described above.

EXAMPLE 3 1-Diethylamino-6-m-acetoxyphenylhex-2-yne

Add 5-m-acetoxyphenylpent-1-yne (9.5 g) to a mixture of trioxan (0.5 g),40% formalin (5.5g), diethylamine (4g), acetic acid (2.75 g), dioxan (25cc), and cuprous chloride (0.13 g) at room temperature. Heat the mixturethus obtained to 70°, to obtain a clear green solution, and maintainunder nitrogen at that temperature for 12 hours. Cool and add ice, pourthe product into ice-cold saturated potassium bicarbonate and extractthe mixture with ether. Wash and dry, evaporate the extracts underreduced pressure and distil to obtain1-diethylamino-6-m-acetoxyphenylhex-2-yne (9.9 g), b.p. 152°-154°/0.1mm, as a pale yellow mobile liquid.

EXAMPLE 4 1-Diethylamino-6-(3,4-methylenedioxyphenyl)-hex-2-yne

Add 5-(3,4-methylenedioxyphenyl)pent-1-yne (24.5 g) in dioxan (15 cc) toa mixture of diethylamine (16 g), trioxan (7.2 g) and cuprous chloride(0.3 g) in dioxan (20 cc) and heat the mixture at 100° for 15 hoursunder an atmosphere of nitrogen. Filter the cooled solution, remove thesolvent and distil the residue at 0.1 mm Hg to obtain1-diethylamino-6-(3,4-methylenedioxyphenyl)-hex-2-yne after a forerun ofmore volatile material.

Infrared absorption peaks at 6.25, 12.20μ.

EXAMPLE 5 1-Diethylamino-6-(3,4-dimethoxyphenyl)-hex-2-yne

Heat a mixture of 5-(3,4-dimethoxyphenyl)-pent-1-yne (8 g), water (2.5cc), trioxan (0.5 g ), 30% formalin (5.5 g), diethylamine (4 g), aceticacid (2.75 g), dioxan (25 cc) and cuprous chloride (0.13 g) at 70° for15 hours. Make the cooled solution alkaline with 10% aqueous sodiumhydroxide and collect the product. Wash the ethereal solution with waterand extract with 10% hydrochloric acid (3 × 30 cc). Wash the combinedaqueous extracts with ether, make it alkaline with 10% sodium hydroxidesolution and extract with ether. Wash and dry the ethereal solution,evaporate the solvent and distil the residue at 0.1 mm Hg to obtain1-diethylamino-6-(3,4-dimethoxyphenyl)-hex-2-yne.

Infrared absorption peaks at 6.25, 12.20 μ.

Prepare 1-diethylamino-6-(3,5-dimethoxyphenyl)-hex-2-yne by treating5-(3,5-dimethoxyphenyl)pent-1-yne with water, trioxan, 30% formalin,diethylamine, acetic acid, dioxan and cuprous chloride according to themanipulative procedure described above.

EXAMPLE 6 1-Diethylamino-6-(3-methoxyphenyl)-hept-2-yne

Heat a mixture of 5-(3-methoxyphenyl)-hex-1-yne (56.6 g), water (17.5cc.), 40% formalin (38.5 cc), diethylamine (40 cc), acetic acid (19 cc),dioxan (175 cc) and cuprous chloride (1 g) at 70° for 16 hours in anatmosphere of nitrogen. Make the cooled solution alkaline with 10%aqueous sodium hydroxide and extract twice with ether. Wash the etherextracts with water, filter and extract with 4N hydrochloric acid (3 ×350 cc). Make the acid extracts alkaline with 10% aqueous sodiumhydroxide, extract with ether and wash the organic solution with water,brine and dry. Evaporate the solvent and distil the residue to obtain1-diethylamino-6-(3-methoxyphenyl)-hept-2-yne, 79.5 g. b.p.135°-140°/0.2 mm Hg n_(D) ²⁵ 1.5116.

C₁₈ H₂₇ ON Calculated: C, 79.07%; H, 9.95%. Found: C, 78.99%; H, 9.67%.

EXAMPLE 7 1-Diethylamino-5-methyl-6-(m-methoxyphenyl)-hex-2-yne

Heat 5-(m-methoxyphenyl)-4-methyl-pent-1-yne (8 g), trioxan (0.5 g), 30%formalin (5.5 cc), diethylamine (4 g), acetic acid (2.75 g), dioxan (25cc) and cuprous chloride (0.12 g) together at 70° for 15 hours. Makecooled solution alkaline with 10% aqueous sodium hydroxide and extractwith ether. Wash the ethereal solution with water and extract with 10%hydrochloric acid (3 × 20 cc). Combine the acid extracts, wash withether and make alkaline with 10% aqueous sodium hydroxide and extractwith ether. Wash the ethereal solution, dry, remove the solvent anddistil the residue at 0.1 mm to obtain1-diethylamino-5-methyl-6-(m-methoxyphenyl)-hex-2-yne.

EXAMPLE 8 1-Diethylamino-6-m-methoxyphenylhexan-3-one and6-m-Methoxyphenylhex-1-en-3-one

Add mercuric sulphate (0.45 g) to a swirled solution of1-diethylamino-6-m-methoxyphenylhex-2-yne (8.5 g) in concentratedsulphuric acid (2.5 cc) and water (25 cc). Keep the solution undernitrogen at 75° C for 1 hour, then cool, make basic with 10% aqueoussodium hydroxide, and filter through glass wool to remove mercuricoxide. Extract product with ether and wash and dry the etherealsolution. Remove the solvent to obtain the crude ketoamine1-diethylamino-6-m-methoxyphenylhexan-3-one, infrared absorption peak at1710 μ. Distil under reduced pressure with partial elimination ofdiethylamine, to obtain a mixture of the ketoamine1-diethylamino-6-m-methoxyphenylhexan-3-one and the vinyl ketone6-m-methoxyphenylhex-1-en-3-one (7.1 g, ca. 76%), b.p. 140°-145° C/0.1mm; infrared absorption peaks at 5.85 and 5.95 μ, the ketoaminepredominating.

Distil a second portion of the crude ketoamine1-diethylamino-6-m-methoxyphenylhexan-3-one very slowly over a period of30 minutes through a Vigreux fractionating column 10 cm high andone-inch diameter under reduced pressure to eliminate most of thediethylamine. Dissolve the 6-m-methoxyphenylhex-1-en-3-one obtained(b.p. 114°-114° C/0.7 mm) in ether and wash the ether solution withdilute hydrochloric acid, followed by aqueous sodium bicarbonate andwater. Dry and evaporate. Distil the residue to give the pure vinylketone as a colorless liquid, b.p. 76° C/0.3 mm.

C₁₃ H₁₆ O₂ Calculated: C, 76.4%; H, 7.9%. Found: C, 76.3%; H, 8.0%.

Mix a third portion of the crude undistilled1-diethylamino-6-m-methoxyphenylhexan-3-one (3g) with methyl iodide (3g). An exothermic reaction soon develops. After 12 hours wash themixture with ether to remove unchanged reactants and subject to reducedpressure (15 minutes) to remove ether remaining: the residue is thecrude methiodide of the ketoamine (4.6 g).

Infrared absorption peaks at 5.85 μ.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 9 1-Diethylamino-6-phenylhexan-3-one and 6-Phenylhex-1-en-3-one

Add to a solution of 1-diethylamino-6-phenylhex-2-yne (27.1 g) inconcentrated sulphuric acid (7.6 cc) diluted with water (77 cc) at 70°mercuric sulphate (1.6 g), and keep the solution under nitrogen for 1hour; cool, make basic with sodium hydroxide solution, and filterthrough glass wool to remove mercuric oxide. Extract the product withether and evaporate the washed and dried ethereal solution, leavingcrude 1-diethylamino-6-phenylhexan-3-one. Distil under reduced pressurewith this ketoamine undergoing partial elimination of diethylamine, toobtain a mixture of the ketoamine, and 6-phenylhex-1-en-3-one (18.9 g),b.p. 96°/0.003 mm.

Infrared absorption peaks at 5.88 and 5.95 μ.

To prepare 1-diethylamino-6-m-ethoxyphenyloctan-3-one and6-m-ethoxyphenyloct-1-en-3-one hydrate and react1-diethylamino-6-m-ethoxyphenyloct-2-yne in the presence of mercurysalts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-propoxyphenylhexan-3-one and6-m-propoxyphenylhex-1en-3-one hydrate and react1-diethylamino-6-m-propoxyphenylhex-2-yne in the presence of mercurysalts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-pentoxyphenylhexan-3-one and6-m-pentoxyphenylhex-1-en-3-one hydrate and react1-diethylamino-6-m-propoxyphenylhex-2-yne in the presence of mercurysalts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-cyclopentyloxyphenylhexan-3-one and6-m-cyclopentyloxyphenylhex-1-en-3-one hydrate and react1-diethylamino-6-m-cyclopentyloxyphenylhex-2-yne in the presence ofmercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-m-propoxyphenylheptan-3-one and6-m-propoxyhept-1-en-3-one hydrate and react1-diethylamino-6-m-propoxyphenylhept-2-yne in the presence of mercurysalts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-(3,5-diethoxyphenyl)hexan-3-one and6-(3,5-diethoxyphenyl)-hex-1-en-3-one hydrate and react1-diethylamino-6-(3,5-diethoxyphenyl)hex-2-yne in the presence ofmercury salts according to the manipulative procedure set forth above.

To prepare 1-diethylamino-6-(3-ethoxy-4-propoxyphenyl)hexan-3-one and6-(3-ethoxy-4-propoxyphenyl)hex-1-en-3-one hydrate and react1diethylamino-6-(3-ethoxy-4-propoxyphenyl)hex-2-yne in the presence ofmercury salts according to the manipulative procedure set forth above.

These compounds are useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 10 1-Diethylamino-6-m-nitrophenylhexan-3-one and6-m-Nitrophenylhex-1-en-3-one

Hydrate 1-diethylamino-6-m-nitrophenylhex-2-yne (1.5 g) using theprocedure of Example 2 with 1/20 of the quantities of reagents. Removethe solvent to obtain crude 1-diethylamino-6-m-nitrophenylhexan-3-one asa clear pale yellow liquid. Distil under reduced pressure, withconsiderable elimination of diethylamine, to obtain crude6-m-nitrophenylhex-1-en-3-one (1 g) as a clear pale yellow liquid.

EXAMPLE 11 1-Diethylamino-6-m-hydroxyphenylhexan-3-one

Add mercuric sulphate (0.27 g) rapidly with swirling to a solution of1-diethylamino-6-m-acetoxyphenylhex-2-yne (3.1 g) in 10% aqueoussulphuric acid (15 cc), and heat the resulting green solution at 75°under nitrogen for 11/2 hours. After cooling, filter to remove mercuricsulphate and add solid potassium bicarbonate until the product has pH8.8. Extract the solution with ether. Wash the other extracts with brinemade alkaline to pH 8.8, and dry over anhydrous magnesium sulphate.Evaporate the ether at room temperature to obtain as residue crude1-diethylamino-6-m-hydroxyphenylhexan-3-one as a viscous brown oil (2.4g), showing infrared absorption at 5.85 μ indicating the presence of aketo group, together with the characteristic band of a phenolic hydroxygroup and the complete absence of a band at 5.68 μ corresponding to aphenolic acetate group.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 12 1-Diethylamino-6-m-acetoxyphenylhexan-3-one and6-m-Acetoxyphenylhex-1-en-3-one

Acetylate the crude 1-diethylamino-6-m-hydroxyphenylhexan-3-one (2.4 g)by adding pyridine (7 cc) and acetic anhydride (3 cc) and allow themixture to stand overnight at room temperature. Work up the mixture asin the acetylation stage described in the preparation of5-m-acetoxyphenylpent-1-yne above, to obtain crude1-diethylamino-6-m-acetoxyphenylhexan-3-one as a viscous brown oil (2.7g).

Infrared absorption peaks at 5.68 μ with a shoulder at 5.85 μ and noappreciable phenolic absorption.

Distil in a Hickman still at 0.1 mm, with partial elimination ofdiethylamine, and collect a colorless mobile liquid, b.p. 160°-170°/0.1mm, which is a mixture (1.8 g) of the ketoamine and6-m-acetoxyphenylhex-1-en-3-one.

Infrared absorption peaks at 5.68, 5.88, 5.95 μ, the nature of theabsorption indicating a predominance of the vinyl ketone in the mixture.

These compounds are useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 13 1-Diethylamino-6-(3,4-dihydroxyphenyl)hexan-3-one

Add mercuric sulphate (0.27 g) to a swirled solution of1-diethylamino-6-(3,4-methylenedioxyphenyl)hex-2-yne (3 g) in 10%aqueous sulphuric acid (15 cc) and heat the mixture for 90 minutes at75° in an atmosphere of nitrogen. Filter the cooled reaction mixture andadd solid potassium carbonate to pH 8.5. Extract the product with ether;wash and dry and evaporate the solvent to leave as residue crude1-diethylamino-6-(3,4-dihydroxyphenyl)hexan-3-one.

Infrared absorption peaks at 5.85 μ.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 14 1-Diethylamino-6-(3,4-dimethoxyphenyl)hexan-3-one and6-(3,4-Dimethoxyphenyl)hex-1-en-3-one

Add mercuric sulphate (0.45 g) to a stirred solution of1-diethylamino-6-(3,4-dimethoxyphenyl)hex-2-yne (8.5 g) in concentratedsulphuric acid (2.5 cc) and water (25 cc) and maintain the solution at75° for 90 minutes. Make the cooled solution basic with 10% aqueoussodium hydroxide and filter to remove mercuric oxide. Extract theproduct with ether and wash and dry the ethereal solution. Evaporate thesolvent to obtain 1-diethylamino-6-(3,4-dimethoxyphenyl)hexan-3-one asan oily residue.

Infrared absorption peaks (liquid film) 5.85 μ. Slowly distil through ashort fractionating column at 0.1 mm Hg to obtain mainly the eliminatedproduct 6-(3,4-dimethoxyphenyl)hex-1-en-3-one.

Infrared absorption peaks (liquid film) 5.95 μ.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 15 1-Diethylamino-6-(3,5-dimethoxyphenyl)hexan-3-one and6-(3,5-Dimethoxyphenyl)hex-1-en-3-one

Proceed exactly as described for the preparation of the 3,4-dimethoxycompound above, using 6-(3,5-dimethoxyphenyl)-1-diethylaminohex-2-yne(8.5 g.), mercuric sulphate (0.45 g), and 10% sulphuric acid (25 cc) toobtain 1-diethylamino-6-(3,5-dimethoxyphenyl)hexan-3-one and6-(3,5-dimethoxyphenyl)hex-1-en-3-one.

EXAMPLE 16 1-Diethylamino-6-(m-methoxyphenyl)heptan-3-one and6-(m-Methoxyphenyl)hept-1-en-3-one

Dissolve 1-diethylamino-6-(m-methoxyphenyl)hept-2-yne (13.6 g) in 10%aqueous sulphuric acid (40 cc) and stir with mercuric sulphate (0.69 g)for 2 hours at 70°. Filter the cooled solution, make basic with 10%aqueous sodium hydroxide and extract with ether. Wash the etherealsolution with water and brine, and dry (Na₂ SO₄). Evaporate the solventand distil the residue to obtain1-diethylamino-6-(m-methoxyphenyl)heptan-3-one which has partiallyeliminated to 6-(m-methoxyphenyl)hept-1-en-3-one during thedistillation, b.p. 145°/12 mm Hg.

Infrared absorption peaks at 5.95 μ.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 17 1-Diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one and5-Methyl-6-(m-methoxyphenyl)hex-1-en-3-one

Add mercuric sulphate (0.45 g) to a stirred solution of1-diethylamino-5-methyl-6-(m-methoxyphenyl)hex-2-yne (8 g) inconcentrated sulfuric acid (2.5 cc) and water (25 cc) and heat themixture at 70° for 11/2 hours. Filter the cooled solution, make basicwith 10% aqueous sodium hydroxide and extract with ether. Wash and drythe ethereal solution and evaporate to leave as residue crude1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one; infraredabsorption peaks at 5.85 μ. Slowly distil at 0.1 mm Hg to obtain5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one; infrared absorption peaks at5.85 μ.

This compound is useful for preparing the novel compositions of thisinvention which have hormonal activity.

EXAMPLE 182-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione

Reflux a mixture (9 g) of 1-diethylamino-6-m-methoxyphenylhexan-3-oneand 6-m-methoxyphenylhex-1-en-3-one with 2-methylcyclohexane-1,3-dione(4 g) in benzene (46 cc) containing pyridine (3.5 cc) for 15 hours. Washand dry the cooled solution. Remove the solvent to obtain the triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione (8.2 g);infrared absorption peaks at 5.88, 5.85, 5.83 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 192-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione

Add to the crude undistilled ketoamine1-diethylamino-6-(m-methoxyphenyl)hexan-3-one (2.3 g), the materialobtained by hydration of the acetylenic amine,2-methylcyclohexane-1,3-dione (1 g), pyridine (1 cc) and benzene (12cc), and reflux the mixture for 15 hours. Cool the mixture and filteroff unreacted dione, add a little ether to the filtrate, and wash theethereal solution with acid, and then water, and dry. Evaporate thesolvents to obtain as residue crude2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione (1.7 g).

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 202-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Reflux a mixture (6 g) of 1-diethylamino-6-m-methoxyphenylhexan-3-oneand 6-m-methoxyphenylhex-1-en-3-one with 2-methylcyclopentane-1,3-dione(2.8 g) in 0.12% dry methanolic potassium hydroxide solution (20 cc) for12 hours. Remove most of the methanol under reduced pressure and add amixture (50 cc) of equal volumes of benzene and ether; wash the solutionwith water, alkali and hydrochloric acid, and dry. Evaporate the solventto obtain the adduct, the triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (6.7 g),a viscous brown gum.

To prepare2-(6-m-methoxyphenyl-3-oxohexyl)-2-n-butylcyclopentane-1,3-dione, treata mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-one and6-m-methoxyphenylhex-1-en-3-one with 2-butylcyclopentane-1,3-dione anddry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare2-(6-m-methoxyphenyl-3-oxohexyl)-2-hydroxypropylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-one and6-m-methoxyphenylhex-1-en-3-one with2-hydroxypropylcyclopentane-1,3-dione and dry methanolic potassiumhydroxide solution according to the manipulative procedure describedabove.

To prepare2-(6-m-ethoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione, treat amixture of 1-diethylamino-6-m-ethoxyphenylhexan-3-one and6-m-ethoxyphenylhex-1-en-3-one with 2-ethylcyclopentane-1,3-dione anddry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare 2-(6-m-propoxyphenyl-3-oxohexyl)-2-phenethylcyclopentane-1,3-dione, treat a mixture of1-diethylamino-6-m-propoxyphenylhexan-3-one and6-m-propoxyphenylhex-1-en-3-one with 2-phenethylcyclopentane-1,3-dioneand dry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare2-(6-m-pentyloxyphenyl-3-oxohexyl)-2-isobutylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-m-pentyloxyphenylhexan-3-one and6-m-pentyloxyphenylhex-1-en-3-one with 2-isobutylcyclopentane-1,3-dioneand dry methanolic potassium hyroxide solution according to themanipulative procedure described above.

To prepare2-(6-m-cyclopentyloxyphenyl-3-oxohexyl)-2-hydroxypropylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-m-cyclopentyloxyphenylhexan-3-oneand 6-m-cyclopentyloxyphenylhex-1-en-3-one with2-hydroxypropylcyclopentane-1,3-dione and dry methanolic potassiumhydroxide solution according to the manipulative procedure describedabove.

To prepare 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-phenethylcyclopentane-1,3-dione, treat amixture of 1-diethylamino-6-m-hydroxyphenylhexan-3-one and6-m-hydroxyphenylhex-1-en-3-one with 2-phenethylcyclopentane-1,3-dioneand dry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepared2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-diethylaminoethylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-(3,4-dimethoxyphenyl)hexan-3-one and6-(3,4-dimethoxyphenyl)hex-1-en-3-one with2-diethylaminoethylcyclopentane-1,3-dione and dry methanolic potassiumhydroxide solution according to the manipulative procedure describedabove.

To prepare2-[6-(3,5-dimethoxyphenyl)-3-oxoheptyl]-2-dimethylaminopropylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-(3,5-dimethoxyphenyl)heptan-3-oneand 6-(3,5-dimethoxyphenyl)hept-1-en-3-one with2-dimethylaminopropylcyclopentane-1,3-dione and dry methanolic potassiumhydroxide solution according to the manipulative procedure describedabove.

To prepare2-[6-(3,5-diethoxyphenyl)-3-oxooctyl]-2-n-butylcyclopentane-1,3-dione,treat a mixture of 1-diethylamino-6-(3,5-diethoxyphenyl)octan-3-one and6-(3,5-diethoxyphenyl)oct-1-en-3-one with 2-butylcyclopentane-1,3-dioneand dry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare2-[6-(3-methoxy-4-ethoxyphenyl)-3-oxohexyl]-2-n-propylcyclopentane-1,3-dione,treat a mixture of1-diethylamino-6-(3-methoxy-4-ethoxyphenyl)hexan-3-one and6-(3-methoxy-4-ethoxyphenyl)hex-1-en-3-one with2-propylcyclopentane-1,3-dione and dry methanolic potassium hydroxidesolution according to the manipulative procedure described above.

To prepare2-(6-m-methoxyphenyl-3-oxohexyl)-2-n-propylcyclopentane-1,3-dione, treata mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-one and6-m-methoxyphenylhex-1-en-3-one with 2-propylcyclopentane-1,3-dione anddry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare2-(6-m-acetoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione, treat amixture of 1-diethylamino-6-m-acetoxyphenylhexan-3-one and6-m-acetoxyphenylhex-1-en-3-one with 2-ethylcyclopentane-1,3-dione anddry methanolic potassium hydroxide solution according to themanipulative procedure described above.

To prepare2-(6-m-hydroxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione, treat amixture of 1-diethylamino-6-m-hydroxyphenylhexan-3-one and6-m-hydroxyphenylhex-1-en-3-one with 2-ethylcyclopentane-1,3-dione anddry methanolic potassium hydroxide solution according to themanipulative procedure described above.

EXAMPLE 212-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Add the crude methiodide of 1-diethylamino-6-m-methoxyphenylhexan-3-one(2.5 g) in methanol (10 cc) ice-cold to a solution obtained by adding2-methylcyclopentane-1,3-dione (0.5 g) to an ice-cold solution of sodium(0.21 g) in methanol (10 cc). Allow the reaction mixture to warm to roomtemperature and leave for 16 hours, after which add N hydrochloric acid(10 cc) and saturated brine (100 cc), and ether-extract the solution.Evaporate the washed and dried extracts to obtain the crude adduct2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as agum.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 222-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Reflux 6-m-methoxyphenylhex-1-en-3-one, containing a small amount of1-diethylamino-6-m-methoxyphenylhexan-3-one (6 g, the material producedby the slow distillation of the latter substance), with2-methylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanol inpotassium hydroxide (10 cc) for 10 hours. Work up the reaction mixtureas described for the preparation of the compound as titled above, toobtain the crude triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (8 g).Distil a small portion of this at 0.02 mm for analysis.

C₁₉ H₂₄ O₄ Calculated: C, 72.1%; H, 7.65% . Found: C, 72.3%; H, 7.45%.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 232-(6-m-Methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Add sodium (0.05 g) to a 0.12% methanolic potassium hydroxide solution(15 cc). To this solution add 1-bromo-6-(m-methoxyphenyl)hexan-3-one(0.9 g) in methanol (5 cc) and 2-methylcyclopentane-1,3-dione (0.4 g),and reflux the mixture for 6 hours. After working up as in thepreparation of the title compound in a previous example, obtain thecrude Michael adduct2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as ayellow gum.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 24 2-(6-m-Methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione

Reflux 2-ethylcyclohexane-1,3-dione (30.6 g), pyridine (20 cc), benzene(372 cc) and a mixture of 1-diethylamino-6-m-methoxyphenylhexan-3-oneand 6-m-methoxyphenylhex-1-en-3-one (40.3 g, produced by thedistillation of the former substance) for 15 hours. Wash the cooledreaction mixture with water, 10% aqueous sulfuric acid, water, 10%aqueous sodium carbonate, water and brine, and filter. Evaporate thesolvent to leave as residue2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione, 38.1 g,56.2%.

This compound is useful as an intermediate for the preparation of thenovel compositions of this invention which have hormonal activity.

EXAMPLE 252-(6-m-Methoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione

Reflux a mixture (5.25 g) of 1-diethylamino-6-m-methoxyphenylhexan-3-oneand 6-m-methoxyphenylhex-1-en-3-one with 2-ethylcyclopentane-1,3-dione(3.3 g) in dry 0.12% methanolic solution of potassium hydroxide for 18hours. Filter the resulting solution, evaporate to dryness and dissolvethe residue in ether. Wash the ether solution with alkali, hydrochloricacid, and water, dry and evaporate to obtain as residue the triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione (7.1 g)as a gum.

This compound is useful as an intermediate for the preparation of thenovel compositions of this invention which have hormonal activity.

EXAMPLE 262-Isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione

Condense a mixture (6 g) of1-diethylamino-6-(m-methoxyphenyl)hexan-3-one and6-(m-methoxyphenyl)hex-1-en-3-one with 2-isopropylcyclopentane-1,3-dione(3 g) using a procedure similar to that described for the condensationof the 2-ethyl compound. Obtain the corresponding triketone,2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2g) as an uncrystallizable gum.

This compound is useful as an intermediate for the preparation of thenovel compositions of this invention which have hormonal activity.

EXAMPLE 272-(6-m-Methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione

Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and1-diethylamino-6-(m-methoxyphenyl)heptan-3-one (10 g, obtained by slowdistillation of the latter substance) with 2-ethylcyclopentane-1,3-dione(7 g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15hours. Remove most of the methanol under reduced pressure and add amixture of equal volumes of ether and benzene (50 cc). Wash the solutionwith 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, andbrine, and dry. Evaporate the solvent to leave as residue the triketoneadduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione(14 g); infrared absorption peak at 5.80 μ.

This compound is useful as an intermediate for the preparation of thenovel compositions of this invention which have hormonal activity.

EXAMPLE 282-Ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione

Add a mixture of 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-oneand 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one (6 g, prepared by slowdistillation of the former substance) to 2-ethylcyclopentane-1,3-dione(3.5 g) in 0.12% methanolic potassium hydroxide (10 cc) and heat themixture under reflux for 16 hours. Remove most of the solvent underreduced pressure and add ether (25 cc) and benzene (25 cc) to theresidue. Wash the solution with 5% aqueous sodium hydroxide, water,dilute hydrochloric acid, and brine, and dry. Evaporate the solvent toobtain a viscous brown gum, which is the triketone2-ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having a hormonal activity.

EXAMPLE 29 2-(6-Phenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione

Reflux the mixture of 1-diethylamino-6-phenylhexan-3-one and6-phenylhex-1-en-3-one (19 g) with 2-methylcyclohexane-1,3-dione (8.4 g)in benzene (97 cc) containing pyridine (7.4 cc) for 15 hours. Wash anddry the cooled solution. Remove the solvent to obtain the crudetriketone 2-(6-phenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 30 2-(6-m-Nitrophenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

6-m-Nitrophenylhex-1-en-3-one (1.0 g, containing a small amount of1-diethylamino-6-m-nitrophenylhexan-3-one) in anhydrous 0.1% methanolicpotassium hydroxide (10 cc) with 2-methylcyclopentane-1,3-dione (1.5 g)for 12 hours. Cool the solution, pour into water and ether extract. Washthe extracts with sodium bicarbonate solution, dry and evaporate toobtain a gum (1.3 g). Crystallize by adding ethanol, recrystallize fromethanaol to obtain2-(6-m-nitrophenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione, m.p.81°-83° C; infrared absorption peaks at 5.70, 5.80, 5.83, 6.54, 7.33 μ(the first three peaks representing carbonyl groups and the others anitro group).

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 312-(6-m-Hydroxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Reflux 1-diethylamino-6-m-hydroxyphenylhexan-3-one (0.72 g) with2-methylcyclopentane-1,3-dione (0.70 g) in 0.12% methanolic potassiumhydroxide (5 cc) for 18 hours. Remove the solvent under reducedpressure. Add chloroform (50 cc) and wash the solution in turn withdilute sulfuric acid, saturated aqueous potassium bicarbonate, andbrine, dry and evaporate the solvent. The product, an amber gum, is theadduct 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione.Infrared absorption peaks at 2.94, 5.71, 5.83 and 5.87 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 322-(6-m-Acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione

Reflux a mixture of 6-(m-acetoxyphenyl)-1-diethylaminohexan-3-one and6-(m-acetoxyphenyl)hex-1-en-3-one (1 g), with2-methylcyclopentane-1,3-dione (1.5 g) in 0.12% methanolic potassiumhydroxide (6 cc) for 18 hours. Remove methanol (2 cc) under reducedpressure and add chloroform (60 cc). Wash the solution in turn withdilute sulfuric acid (25 cc), saturated potassium bicarbonate solution,and brine; dry and evaporate the solvent. The product (0.8 g) is theadduct 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dionein admixture with some of the corresponding free phenol; infraredabsorption: 2.86 to 3.08 (broad low-intensity band), 5.71, 5.81, 5.85,and 8.26 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 332-(6-m-Hydroxyphenyl-3-oxohexyl)-2-n-propylcyclopentane-1,3-dione

Heat together 2-n-propylcyclopentane-1,3-dione (13 g),1-diethylamino-6-m-hydroxyphenylhexan-3-one and 0.12% methanolicpotassium hydroxide solution (38 cc) under gentle reflux for 12 hours.Isolate the product to obtain the Michael adduct,2-(6-m-hydroxyphenyl-3-oxohexyl)-2-n-propylcyclopentane-1,3-dione as abrown gum (7.18 g).

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 342-[6-(3,4-Dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione

Reflux 6-(3,4-dimethoxyphenyl)hex-1-en-3-one, containing a small amountof 6-(3,4-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced byslow distillation of the latter substance) with2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolicpotassium hydroxide (10 cc) for 10 hours. Remove most of the methanolunder reduced pressure, add benzene (25 cc) and ether (25 cc) and washthe solution with water, dilute aqueous potassium hydroxide, dilutehydrochloric acid and water. Dry and evaporate the solvent to give thetriketone adduct2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione;infrared absorption (gum) 5.80, 6.25 μ (split peak).

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 352-[6-(3,5-Dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione

Reflux 6-(3,5-dimethoxyphenyl)hex-1-en-3-one, containing a small amountof 6-(3,5-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced byslow distillation of the latter substance) with2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolicpotassium hyroxide (10 cc) for 10 hours. Work up the reaction mixture asfor the preparation of 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione to obtain2-[6-(3,5-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione asa viscous gum; infrared absorption peaks at 5.80, 6.25 μ (split peak).

This compound is useful as an intermediate for preparing the novelcompositions of this invention having hormonal activity.

EXAMPLE 36 Diethyl2-(6-m-methoxyphenyl-3-oxohexyl)-2-methyl-3-oxoadipate

Stir a mixture of diethyl 2-methyl-3-oxoadipate (2.3 g, b.p. 111°-112°C/0.2 mm), prepared from 2- methylacetoacetic ester andethoxycarbonylpropionyl chloride by the method of Cardwell, J. Chem.Soc., 1949, 715, and the methiodide of1-diethylamino-6-m-methoxyphenylhexan-3-one (4.6 g) in benzene (20 cc)in an ice bath and add a solution of potassium (0.4 g) in ethanol (10cc) dropwise over one hour. After stirring for a further 4 hours addether (50 cc) and evaporate the washed and dried ether extracts. Heatthe residue at 160°C and 0.2 mm pressure to remove unchanged startingmaterials. The residual gum is diethyl2-(6-m-methoxyphenyl-3-oxohexyl)-2-methyl-3-oxoadipate (2.7 g); infraredabsorption peaks at 5.78, 5.88, 6.25, 12.82, 14.49 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 3713β-Methyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17a-one

Reflux the dicyclic triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclohexane-1,3-dione (2 g) for2 hours in benzene (35 cc) containing anhydrous toluene-p-sulfonic acid(1 g) using a Dean-Stark trap to remove the water formed. The worked-upproduct is a solid which one recrystallizes from light petroleum (b.p.60°-80°) and from methanol to give the diene13β-methyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17a-one (0.5 g),m.p. 135°-137° C; ultraviolet absorption peak at 310 mμ (ε30,000).

C₂₀ H₂₂ O₂ Calculated: C, 81.6%; H, 7.5%. Found: C, 81.45%; H, 7.7%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 38 13β-Methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Dissolve the triketone2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (6.7 g),in dry benzene (100 cc) containing anhydrous toluene-p-sulfonic acid(2.4 g). Reflux the mixture using a Dean-Stark water separator until theequivalent of two molecular proportions of water (0.99 cc) is collected(30 minutes), indicating a double cyclodehydration. Cool and wash toremove acid, and dry. Evaporate the dried solution to obtain a red gum.Distil the gum under reduced pressure (bath temperature 210°, 0.5 mm).Recrystallize the solidified distillate from methanol, giving13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (3.9 g), m.p.115°-116°; ultraviolet absorption peak at 313 mμ (ε35,100). The lightabsorption is in agreement with the structure assigned.

C₁₉ H₂₀ O₂ Calculated: C, 81.4%; H, 7.2%. Found: C, 81.1%; H, 7.0%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 39 13β-Methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Add the crude methiodide of 1-diethylamino-6-m-methoxyphenylhexan-3-one(2.5 g) in methanol (10 cc) ice-cold to a solution obtained by adding2-methylcyclopentane-1,3-dione (0.5 g) to an ice-cold solution of sodium(0.21 g) in methanol (10 cc). Allow the reaction mixture to warm to roomtemperature and leave for 16 hours, after which add N hydrochloric acid(10 cc) and saturated brine (100 cc), ether-extracting the solution.Evaporate the washed and dried extracts to obtain crude2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as agum; dissolve in benzene (25 cc) containing toluene-p-sulfonic acid (0.4g) and reflux the mixture for 1 hour. Cool, add ether (25 cc), and wash,dry, and evaporate the solution. Take up the resulting gum in benzene (5cc) and adsorb on a column of Fuller's earth (100 g). Elute with amixture of benzene and light petroleum to obtain a series of fractions,one of which crystallizes (0.04 g). Boil this fraction with methanol anddecant the solution from insoluble oil which forms. Reduce the solutionin bulk by evaporation, depositing crystals on cooling; recrystallizefrom methanol to obtain 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 111°-113° C; ultraviolet absorption peak at 312 mμ(ε34,800).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 40 13β-Methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

To 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (3 g)in benzene (100 cc) add polyphosphoric acid (from orthophosphoric acid,15 g. and phosphorus pentoxide, 6 g.) and heat the mixture at 90° for 4minutes under such reduced pressure as the need to control frothing willallow. Cool, add water, and extract the mixture with ether and ethylacetate; isolate the product from the resulting solution to obtain thecolorless crystalline 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g), b.p. 115°-116°; ultraviolet absorption peakat 313 mμ (ε35,100).

To prepare13β-(3-hydroxypropyl)-3-methoxygona-1,3,5(10),8,14-pentaen-17-one treat2-(6-m-methoxyphenyl-3-oxohexyl)-2-(3-hydroxypropyl)cyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare 13β-phenethyl-3-propoxygona-1,3,5(10),8,14-pentaen-17-onetreat 2-(6-m-propoxyphenyl-3-oxohexyl)-2-phenethylcyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare 13β-isobutyl-3-pentyloxygona-1,3,5(10),8,14-pentaen-17-onetreat2-(6-m-pentyloxyphenyl-3-oxohexyl)-2-isobutylcyclopentane-1,3-dione withpolyphosphoric acid according to the manipulative procedure describedabove.

To prepare13β-(3-hydroxypropyl)-3-cyclopentyloxygona-1,3,5(10),8,14-pentaen-17-onetreat2-(6-m-cyclopentyloxyphenyl-3-oxohexyl)-2-(3-hydroxypropyl)cyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare 13β-phenethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-onetreat 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-phenethylcyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare13β-(2-diethylaminoethyl)-2,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-onetreat2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-(2-diethylaminoethyl)cyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare13β-(3-dimethylaminopropyl)-1,3-dimethoxy-6-methylgona-1,3,5(10),8,14-pentaen-17-onetreat2-[6-(3,5-dimethoxyphenyl)-3-oxoheptyl]-2-(3-dimethylaminopropyl)cyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare13β-butyl-1,3-diethoxy-6-ethylgona-1,3,5(10),8,14-pentaen-17-one treat2-[6-(3,5-diethoxyphenyl)-3-oxooctyl]-2-butylcyclopentane-1,3-dione withpolyphosphoric acid according to the manipulative procedure describedabove.

To prepare13β-propyl-2-ethoxy-3-methoxygona-1,3,5(10),8,14-pentaen-17-one treat2-[6-(3-methoxy-4-ethoxyphenyl)-3-oxohexyl]-2-propylcyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

To prepare13β,6-dimethyl-1,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one treat2-[6-(3,5-dimethoxyphenyl-3-oxoheptyl]-2-methylcyclopentane-1,3-dionewith polyphosphoric acid according to the manipulative proceduredescribed above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

EXAMPLE 41 13β-Methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Heat the tricyclic diketone5,6,7,8-tetrahydro-4-m-methoxyphenethyl-8-methylindane-1,5-dione (0.25g), under nitrogen at 60° with a mixture of orthophosphoric acid (5 cc,S.G. 1.8) and phosphorus pentoxide (3.25 g) for 20 minutes. Work up bymeans of ether to obtain a partially crystalline product which one takesup in benzene (10 cc) and filters. Recrystallize the residue to obtainthe diene 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (0.6g), m.p. 110°-112° C; ultraviolet absorption peaks at 310 mμ (ε37,200);infrared absorption peak at 5.78 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 42 13β-Ethyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17a-one

Add 2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclohexane-1,3-dione (32.8g) in benzene (400 cc) to polyphosphoric acid (150 g) in an atmosphereof nitrogen and stir the mixture at 60° for 3 hours. Add water, separatethe benzene layer and wash with water until neutral. Dry the solution,remove the solvent, and recrystallize the residue from ethanol to obtain13β-ethyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17 a-one, m.p.90°-92°; ultraviolet absorption peak at 311 mμ (ε28,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 43 13β-Ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Reflux the triketone2-ethyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.1 g),in benzene (150 cc) and toluene-p-sulfonic acid (2 g) until thetheoretical amount of water (0.72 cc) for double cyclodehydration hasbeen collected in a Dean-Stark separator. Wash the cooled reactionmixture after removal of solvent under reduced pressure, b.p. ca.220°/0.01 mm, to obtain an almost colorless glass (5.7 g). Crystallizethe glass from methanol containing a little ethyl acetate to obtain pure13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (3.7 g), m.p.77°-80°; ultraviolet absorption peak at 311 mμ (ε28,000).

C₂₀ H₂₂ O₂ Calculated: C, 81.6%; H, 7.5%. Found: C, 81.3%; H, 6.3%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 44 13β-Propyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Condense 2-propylcyclopentane-1,3-dione (13.1 g) in 0.12% methanolicpotassium hydroxide solution (90 cc) with6-m-methoxyphenyl-hex-1-en-3-one (19.0 g), to obtain crude2-n-propyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (25.5g). Submit this Michael condensation product (23.4 g) to doublecyclodehydration by heating with toluene-p-sulfonic acid, and distil theproduct at 200°/10⁻ ⁴ mm; crystallize the distillate from ethanol toobtain the tetracyclic diene ketone13β-propyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 82°-84°;ultraviolet absorption peak at 310 mμ (ε24,700).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 45 13β-Isopropyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Reflux the triketone2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2g) in benzene (150 cc) and toluene-p-sulfonic acid (2 g) until thetheoretical amount of water (0.72 cc) for double cyclodehydration hasbeen collected in a Dean-Stark trap. Wash the cooled reaction mixture toremove acid and dry. Remove the solvent to obtain a gum. Distil the gumto obtain a glass (5 g), which one crystallizes from methanol to obtainpure 13β-isopropyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (4.5g),m.p. 112°-113°.

C₂₁ H₂₄ O₂ Calculated: C, 81.8%; H, 7.8%. Found: C, 81.8%; H, 7.6%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 46 13β-Butyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Condense n-butylcyclopentane-1,3-dione (2.8 g) in 0.12% methanolicpotassium hydroxide solution (8 cc) with 6-m-methoxyphenylhex-1-en-3-one(5 g) by heating the mixture at 80° for 10 hours. Evaporate the solventunder reduced pressure and heat the residue with toluene-p-sulfonic acid(2 g) in benzene (50 cc) for 45 minutes using a Dean-Stark trap toeffect double cyclodehydration. Add ether to the cooled reactionmixture, and evaporate the washed and dried ether solution;recrystallize the residue from ethanol to obtain13β-butyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (1.9 g), m.p.53°-55°; ultraviolet absorption peak at 312 mμ (ε29,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 47 13β-Isobutyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Reflux a mixture of crude2-(6-m-methoxyphenyl-3-oxohexyl)-2-isobutyl-1,3-cyclopentanedione (154.9g) and anhydrous p-toluene-sulfonic acid (177 g) in 5.2 liters of drybenzene for 3 hours using a Dean-Stark water separator. After cooling,filter the solution, wash, dry, and concentrate to 1/3 of its volume.Then filter through charcoal (Carco, 310 g). Distil the filtrate toobtain a viscous oil, b.p. 203° (bath temperature), 0.01 mm.Recrystallize from methanol-acetone to get13β-isobutyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 57°-60°;ultraviolet absorption peak at 312 mμ (ε 25,200).

C₂₂ H₂₆ O₂ Calculated: C, 81.9%; H, 8.1%. Found: C, 81.6%; H, 8.1%.

This compound has estrogenic activity, lowers the blood lipid level andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 48 13β-Cetyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one

Reflux a mixture of 2-cetylcyclopentane-1,3-dione (10.1 g),6-m-methoxyphenylhex-1-en-3-one (6.0 g) and 0.02% methanolic potassiumhydroxide solution (120 cc) for 26 hours and then cool. Dissolve theresidue obtained after removal of solvent under reduced pressure in amixture of benzene (50 cc) and ether (50 cc), and wash the solution inturn with sodium carbonate solution, 10% aqueous sulfuric acid andwater. Remove the solvent by evaporation under reduced pressure toobtain as residue crude2-cetyl-2-(6-m-methoxyphenyl-3-oxohexyl)-1,3-cyclopentanedione (11.4 g).

Add a solution of this Michael condensate in dry benzene (80 cc) to amixture of anhydrous toluene-p-sulfonic acid (2.4 g) and dry benzene (80cc) and reflux the mixture for one hour, using a Dean-Stark waterseparator, until the equivalent of 2 moles of water (0.75 cc) has beencollected. Wash the cooled solution, dry, and remove the solvent,leaving a purple oil (10.2 g) which one then distils at about 220°/0.001mm. Recrystallize the solidified distillate from acetonitrile, to obtain13β-cetyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 55°-56° C;ultraviolet absorption peak at 316 mμ (ε24,000).

C₃₄ H₅₀ O₂ Calculated: C, 83.2%; H, 10.3%. Found: C 83.3%; H, 10.3%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 4913β-Ethyl-3-methoxy-6-methylgona-1,3,5(10),8,14-pentaen-17-one

Reflux 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane- 1,3-dione(14 g) with anhydrous toluene-p-sulfonic acid (4 g) in benzene (50 cc)with continuous water separation for 20 minutes. Wash the cooledsolution with water, dry, and evaporate the solvent. Distil the residualred gum to obtain13β-ethyl-3-methoxy-6-methylgona-1,3,5(10),8,14-pentaen-17-one as a gum;ultraviolet absorption peak at 315 mμ (ε21,000); infrared absorptionpeak at 5.75 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 5013β-Ethyl-3-methoxy-7-methylgona-1,3,5(10),8,14-pentaen-17-one

Dissolve the crude triketone2-ethyl-2-(6-m-methoxyphenyl-5-methyl-3-oxohexyl)cyclopentane-1,3-dione(3 g) in benzene (50 cc) containing anhydrous toluene-p-sulfonic acid(1.5 g) and reflux the mixture with continuous water separation for 45minutes. Dilute the cooled solution with ether, and wash with water; dryand evaporate. Distil the red residue at 230° (bath temperature) at 0.02mm to give13β-ethyl-3-methoxy-7-methylgona-1,3,5(10),8,14-pentaen-17-one; infraredabsorption peak at 5.78 μ; ultraviolet absorption peak at 310 mμ(ε25,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 51 13β-Methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Reflux 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione(0.5 g), the product of Michael condensation of2-methylcyclopentane-1,3-dione with6-m-hydroxyphenyl-1-diethylaminohexan-3-one, for 50 minutes in benzene(30 cc) containing toluene-p-sulfonic acid (0.3 g) using a Dean-Starktrap. Add ether (80 cc) to the cooled product and filter off theresulting insoluble material. Wash the ethereal solution in turn withwater, saturated aqueous potassium bicarbonate, and brine, and dry. Theproduct is a deep green gum which one takes up in a small quantity ofether; precipitate the insoluble impurities by the addition of lightpetroleum and filter off. Evaporate the resulting solution to obtain acrystalline residue, which one takes up in a mixture of benzene (10 cc)and ether (2 cc); adsorb the solution on an activated Fuller's earth (10g). Elute with benzene to obtain13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.19 g), m.p.225° (decomp.).

C₁₈ H₁₈ O₂ Calculated: C, 81.2% H, 6.8%. Found: C, 80.7%; H, 7.0%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 52 13β-Methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Allow 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione(0.8 g) to stand for 90 minutes at room temperature in benzene (80 cc)containing anhydrous toluene-p-sulfonic acid (5 g). Wash the productwith water, followed by aqueous sodium bicarbonate solution, and dry.Remove the solvent by evaporation to obtain a deep green gum;ultraviolet absorption peak at 313 mμ (13,000). When this gum is seededit becomes solid. Take up the crude material in benzene (15 cc) andadsorb the solution on an activated Fuller's earth (30 g); elute withbenzene to obtain pale yellow 13β-methyl-3-hydroxy-gona-1,3,5(10),8,14-pentaen-17-one (0.6 g).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 53 13β-Methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Reflux 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione(0.8 g, the product of Michael condensation of 2-methylcyclopentanedioneand a mixture of 6-m-acetoxyphenyl-1-diethylaminohexan-3-one and6-m-acetoxyphenylhex-1-en-3-one, and containing some of thecorresponding free phenolic compound) in benzene (25 cc) withtoluene-p-sulfonic acid (0.3 g) for 50 minutes. On cooling add ether (50cc) and wash the mixture in turn with water, saturated aqueous potassiumbicarbonate, and brine; dry over anhydrous magnesium sulfate. Theresidue after removal of solvent is a purple gum (0.6 g), part of whichcan be induced to crystallize. Dissolve a portion (0.45 g) of this gumin benzene and adsorb on an activated Fuller's earth (40 g); elute withbenzene to obtain13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one, which onerecrystallizes from diisopropyl ether, m.p. 225°-226°; ultravioletabsorption peak at 312.5 mμ (ε23,000); infrared absorption peaks at 2.99μ, 5.81 μ, and 8.00μ. This compound has estrogenic activity, lowers theblood lipid level, and is useful as an intermediate for preparing thehormonal compounds of this invention.

EXAMPLE 54 13β-Methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Place 300 g. of warm polyphosphoric acid in a 1 liter flask fitted withdropping funnel, stirrer and thermometer. Add crude2-(6-m-hydroxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione Michaeladduct (28.3 g), dissolved by warming in dry benzene (70 cc) dropwisewith stirring during 45 minutes to the acid at 40°-50°. Stir the mixturefor a further 45 minutes by which time it becomes a very deep red. Addcrushed ice with vigorous stirring and extract the resulting mixturewith ether (3 × 250 cc). A small quantity of black tar remains insolublein either phase. Wash the combined ethereal extracts with saturatedKHCO₃ and brine, and then dry (MgSO₄). Remove the solvent on the rotaryevaporator (temperature not greater than 40°) to obtain a bright yellowcrystalline solid. Wash by decantation with cold 20% ethyl acetate60°-80° petroleum ether (20 cc), filter and dry to obtain crude13β-methyl-3-hydroxy-gona-1,3,5(10),8,14-pentaen-17 -one (19.35 g.,77%), m.p. 160°-162° (dec.); ultraviolet absorption peak at 312 mμ,(ε22,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 55 13β-Methyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one

Mix 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one with pyridine(3 cc) and acetic anhydride (1 cc) and keep at room temperature for 4hours. Add ethanol (1 cc) and remove low-boiling material under reducedpressure (0.1 mm) to leave a red gum which crystallizes from a mixtureof ethyl acetate and light petroleum. Recrystallize from methanol toobtain crystals of13β-methyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, meltingpartially at 161°-166° with resolidification at about 220° and finallymelting at 260°-265° (decomp.); infrared absorption peaks at 5.75 μ and8.27 μ, with absence of an absorption band due to a hydroxy group;ultraviolet absorption peak at 307.5 mμ (ε24,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 56 13β-Ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Reflux 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione(2.6 g) for 30 minutes in benzene (70 cc) containing toluene-p-sulfonicacid (0.38 g), and collect the water evolved in the cyclodehydration ina Dean-Stark separator. Work up to obtain a green gum which onedissolves in benzene (30 cc); adsorb the benzene solution on a column ofactivated Fuller's earth, and elute with benzene to obtain crude13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.75 g), as paleyellow crystals, m.p. 153°-156°; ultraviolet absorption peak at 313.5 mμ(ε30,300); infrared absorption peaks at 3.99 μ and 5.81 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 57 13β-Ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Allow 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione(8.8 g) to stand 24 hours at room temperature in solution in benzene(430 cc) containing anhydrous toluene-p-sulfonic acid (20 g). Work upthe product to obtain a deep red and green gum; take up in benzene (50cc) and adsorb on activated Fuller's earth (300 g). Elute with benzeneto obtain pale green crystals of crude13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (2.05 g) m.p.149°-151°, the substance melting to a clear liquid on rapid heating;ultraviolet absorption peak at 314 mμ (ε30,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 58 13β-Ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Add 2-(6-m-hydroxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione (28.3g) in benzene (70 cc) during 45 minutes to polyphosphoric acid (300 g)containing 80% phosphorus pentoxide, and maintain at 40°-50°, withstirring. Stir the reaction mixture for a further 45 minutes duringwhich it develops a deep red coloration. Add crushed ice and extract theproduct with ether. Evaporate the washed and dried extracts at atemperature not greater than 40° to obtain a bright yellow crystallinesolid; wash by decantation with light petroleum containing a smallproportion of ether; filter and dry to obtain13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (19.35 g), m.p.160°-162°; ultraviolet absorption peak at 312 mμ (ε22,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 59 13β-Ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Add a solution of2-(6-m-acetoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-1,3-dione (18.0 g)in benzene (40 cc) during 11/2 hours to stirred polyphosphoric acid (180g., containing 80% phosphorus pentoxide) and maintain at 40°-42°. Keepthe reaction mixture at this temperature for a further hour withoccasional stirring, add ice and water, and extract the product withether. Evaporate the washed and dried extracts under reduced pressure toobtain a crude solid product (13.4 g), containing13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one and its 3-acetatein a proportion indicated by spectroscopic analysis to be 7:3;ultraviolet absorption peak at 312 mμ (ε12,700).

This 3-hydroxy compound has estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 60 13β-Ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one

Dissolve 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (2.45 g)in pyridine (7 cc) and acetic anhydride (4 cc) and allow to stand atroom temperature for 16 hours. Remove the solvent under reducedpressure, add ethanol (20 cc) and again evaporate the solvent.Recrystallize the residue from ethanol to give a red crystalline solid,m.p. 122°-124°. Filter the solid through `Florisil` (100 g) withbenzene, evaporate the solvent and recrystallize the product fromethanol to obtain 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one,m.p. 129°-130°C; ultraviolet absorption peak at 306 mμ (ε25,500),infrared absorption peaks at 5.78 μ, 8.27 μ, and 9.85 μ.

C₂₁ H₂₂ O₃ Calculated: C, 78.25%; H, 6.9%. Found: C, 78.4%; H, 6.65%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 61 13β-Propyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one

Cyclodehydrate2-(6-m-hydroxyphenyl-3-oxohexyl)-2-n-propylcyclopentane-1,3-dione (7.18g) by heating in benzene (210 cc) containing toluene-p-sulfonic acid(0.75 g), to obtain a deep green gum (6.4 g); chromatograph in benzeneon a column of activated Fuller's earth, to give a yellow gum.Crystallize from ethanol, and then from a mixture of benzene and lightpetroleum to obtain13β-propyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.59 g), m.p.149°-155° with some premelting at 135°-138°; ultraviolet absorption peakat 313 mμ (ε27,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 62 13β-Ethyl-2,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one

Dissolve the crude triketone2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione(6.5 g) in dry benzene (100 cc) containing anhydrous toluene-p-sulfonicacid (2.4 g) and reflux under a Dean-Stark water separator for 45minutes. Wash the cooled solution with water, sodium carbonate solution,and water, and dry. Evaporate the solvent and distil the red gummyresidue at 220° (bath temperature) 0.01 mm. to give a yellow gum;recrystallize from methanol to obtain13β-ethyl-2,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one; ultravioletabsorption peak at 314 mμ (ε29,000); infrared absorption peaks at 5.84 μand 8.00 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 63 13β-Ethyl-1,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one

Using the triketone2-[6-(3,5-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione(6.5 g), proceed exactly as described in the preceeding example toobtain 13β-ethyl-1,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one;infrared absorption peaks at 5.74 μ and 8.00 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 64 13β-Methyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17a-one

To 13β-methyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17a-one (0.3g) in dioxan (20 cc) add a moderately active Raney nickel catalyst (ca.0.2 g). Hydrogenate at room temperature and atmospheric pressure until24 cc. hydrogen has been absorbed. Filter off the catalyst and evaporatethe filtrate to obtain a solid; recrystallize from a mixture of ethanoland ethyl acetate to obtain the title product (0.15 g), m.p. 120°-150°C. Ultraviolet absorption peak at 275 mμ (ε14,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 65 13β-Methyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Dissolve 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (1 g) indioxan (33 cc). To the solution add Raney nickel catalyst (ca. 0.5 g)which has been prepared by the method of Pavlic and Adkins, J. Amer.Chem. Soc., 1946, 68, 1471 and allow to stand for 24 hours. Hydrogenateat room temperature and pressure until the theoretical amount ofhydrogen (92 cc) for saturation of one ethylenic linkage has beenabsorbed. Towards the end of this period (5 hours) the rate ofhydrogenation drops markedly. Evaporate the solvent after removal ofcatalyst to obtain a gum which readily crystallizes. Recrystallize oncefrom ethanol to obtain the crude title product (0.69 g), m.p. 110°-120°;ultraviolet absorption peak at 278 mμ (ε14,700).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 66 13β-Methyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Shake 13β-methyl-3 -methoxygona-1,3,5(10),8,14-pentaen-17-one (1 g) inbenzene (35 cc) with a 10% palladium or barium sulfate catalyst (0.3 g)in the presence of hydrogen at atmospheric pressure until 90 cc hydrogenhas been absorbed. By the end of this period (11/2 hours) the rate ofhydrogenation will have slowed down. Filter the mixture and evaporatethe solvent to obtain a gum which solidifies; recrystallize from ethanolto obtain the title product (0.68 g), m.p. 110°-120°; ultravioletabsorption peak at 278 mμ (ε13,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 67 13β-Ethyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17 a-one

Shake 13β-ethyl-3-methoxy-D-homogona-1,3,5(10),8,14-pentaen-17 a-one(1.175 g) in tetrahydrofuran (100 cc) with 2% palladium on calciumcarbonate (0.5 g., prereduced) in an atmosphere of hydrogen until onemolecular equivalent of hydrogen has been absorbed. Filter the catalyst;evaporate the solvent; recrystallize the residue from ethanol to obtainthe title product (0.925 g), m.p. 104°-107°; ultraviolet absorption peakat 278 mμ (ε15,680).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 68 13β-Ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Dissolve 13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) indioxan (50 cc) containing Raney nickel (ca. 0.5 g) of moderate activityand shake with hydrogen until 160 cc., the amount corresponding to onemolecular proportion has been absorbed. Recrystallize the isolatedproduct from methanol to obtain the title product (1.2 g), m.p.110°-125°; ultraviolet absorption peak at 280 mμ (ε13,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 69 13β-Propyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Condense 2-propyl-1,3-cyclopentanedione (13.1 g) in 0.12% methanolicpotassium hydroxide solution (90 cc) with6-m-methoxyphenylhex-1-en-3-one (19.0 g), to obtain crude2-propyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (25.5g). Submit this Michael condensation product (23.4 g) to doublecyclodehydration; distil the product at 200°/10⁻ ⁴ mm. and crystallizethe distillate from ethanol, to obtain the tetracyclic diene ketone,m.p. 82°-84°; ultraviolet absorption peak at 310 mμ (ε24,700).

Selectively hydrogenate the diene ketone (5 g) in benzene solution witha palladium on calcium carbonate catalyst until sufficient hydrogen hasbeen taken up to saturate the 14,15-ethylenic bond. Isolate the product(3.5 g) as pink crystals from methanol, m.p. 111°-113°.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 70 13β-Isopropyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Shake 13β-isopropyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) indioxan (50 cc) with a freshly prepared but moderately active Raneynickel catalyst (ca. 0.5 g) in hydrogen at atmospheric pressure. When,after several hours the theoretical amount of hydrogen forhalf-hydrogenation (160 cc) has been absorbed, filter off the nickelcatalyst and remove the solvent by evaporation. Crystallize the residualgum from methanol to obtain the title product (1.2 g), m.p. 85°-100°C;ultraviolet absorption peak at 280 mμ (ε11,800).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 71 13β-Butyl-3-methoxygona-1,3,5(10), 8-tetraen-17-one

Condense 2-butyl-1,3-cyclopentanedione (2.8 g) in 0.12% methanolicpotassium hydroxide solution (8 cc) with 6-m-methoxyphenylhex-1-en-3-one(5 g) by heating the mixture at 80° for 10 hours. Evaporate the solventunder reduced pressure and heat the residue with toluene-p-sulfonic acid(2 g) in benzene (50 cc) for 45 minutes using a Dean-Stark trap, toeffect double cyclodehydration. Add ether to the cooled reaction mixtureand evaporate the washed and dried ether solution; recrystallize theresidue from ethanol to obtain the tetracyclic diene (1.9 g), m.p.53°-55°; ultraviolet absorption peak at 312 mμ (ε29,200).

Shake this tetracyclic diene (1.38 g) in benzene (45 cc) in hydrogen atatmospheric pressure with a previously reduced 2% palladium on calciumcarbonate catalyst (0.5 g). When 100 cc. hydrogen has been absorbeddiscontinue the hydrogenation and filter off the catalyst. Evaporatesolvent and recrystallize the residue from methanol to obtain the titleproduct (1.02 g), m.p. 105°-108°; ultraviolet absorption peak at 278 mμ(ε16,700).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 72 13β-Isobutyl-3-methoxygona-1,3,5(10), 8-tetraen-17-one

To a pre-reduced suspension of 2% palladium on calcium carbonatecatalyst (7.0 g) in benzene (30 cc) add a solution of13β-isobutyl-3-methoxygona-1,3,5(10), 8,14-pentaen-17-one (20.0 g) inbenzene (500 cc) and hydrogenate the mixture at atmospheric pressureuntil one mole equivalent of hydrogen is consumed. After the catalyst isremoved by filtration, evaporate the solvent to obtain a gum which oncrystallization from ethanol affords the title product (17.1 g.; 71%),m.p. 117°-119°; ultraviolet absorption peak at 278 mμ (ε14,560).

To prepare 6,13β-dimethyl-3-methoxygona-1,3,5(10), 8-tetraen-17-onehydrogenate 6,13β-dimethyl-3-methoxygona-1,3,5(10), 8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 7,13β-dimethyl-3-methoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 7,13β-dimethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13β-ethyl-1,3-dimethoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-ethyl-1,3-dimethoxygona-1,3,5(10), 8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13β-ethyl-3-acetoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one over a2% palladium on calcium carbonate catalyst in benzene according to themanipulative procedure described above.

To prepare 13β-(3-hydroxypropyl)-3-methoxygona-1,3,5(10),8-tetraen-17-one hydrogenate13β-(3-hydroxypropyl)-3-methoxygona-1,3,5(10),8,14-pentaen-17-one over a2% palladium on calcium carbonate catalyst in benzene according to themanipulative procedure described above.

To prepare 13β-ethyl-3-ethoxygona-1,3,5(10), 8-tetraen-17-onehydrogenate 13β-ethyl-3-ethoxygona-1,3,5(10), 8,14-pentaen-17-one over a2% palladium on calcium carbonate catalyst in benzene according to themanipulative procedure described above.

To prepare 13β-phenethyl-3-propoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-phenethyl-3-propoxygona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13β-isobutyl-3-pentyloxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-isobutyl-3-pentyloxygona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare13β-(3-hydroxypropyl)-3-cyclopentyloxygona-1,3,5(10),8-tetraen-17-onehydrogenate13β-(3-hydroxypropyl)-3-cyclopentyloxygona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13β-phenethyl-3-hydroxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-phenethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare13β-(2-diethylaminoethyl)-2,3-dimethoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-(2-diethylaminoethyl)-2,3-dimethoxygona-1,3,5(10),8,14-pentaen-17-one over a 2% palladium on calcium carbonate catalyst inbenzene according to the manipulative procedure described above.

To prepare13β-(3-dimethylaminopropyl)-1-methoxy-3-ethoxy-6-methylgona-1,3,5(10),8-tetraen-17-onehydrogenate13β-(3-dimethylamino-propyl)-1-methoxy-3-ethoxy-6-methylgona-1,3,5(10),8,14-pentaen-17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13β-propyl-2-ethoxy-3-methoxygona-1,3,5(10),8-tetraen-17-onehydrogenate 13β-propyl-2-ethoxy-3-methoxygona-1,3,5(10),8,14-pentaen-17-one over a 2% palladium on calcium carbonate catalyst inbenzene according to the manipulative procedure described above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

EXAMPLE 73 13β-Cetyl-3-methoxygona-1,3,5(10),8-tetraen-17-one

Hydrogenate 13β-cetyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2.39g) in benzene (140 cc) at atmospheric pressure with a previously reduced2% palladium oxide on calcium carbonate catalyst (0.3 g) until onemolecular equivalent of hydrogen has been absorbed. Remove the catalystand evaporate to obtain a residue which one crystallizes from ethanol toobtain the title product (2.4 g), as colorless crystals, m.p. 54°-56°;ultraviolet absorption peak at 278 mμ(ε11,500).

C₃₄ H₅₂ O₂ Calculated: C, 82.85%; H, 10.65%. Found: C, 82.75%; H,10.75%.

This compound has estrogenic activity and is useful as an intermediatefor preparing the hormonal compounds of this invention.

EXAMPLE 74 13β-Methyl-3-hydroxygona-1,3,5(10),8-tetraen-17-one

Hydrogenate 13β-methyl-3-acetoxygona-1,3,5(10),8,14 -pentaen-17-one(0.05 g), obtained by the acetylation of13βmethyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one using pyridineand acetic anhydride in benzene (15 cc) at atmospheric pressure using a10% palladized charcoal catalyst (0.025 g). Hydrogenation slows downmarkedly after the requisite quantity of hydrogen for monohydrogenationhas been absorbed. Remove the catalyst by filtration and evaporate thesolvent to obtain as residue the crude title product.

Immediately take the product up in methanol (4 cc), add 3N sodiumhydroxide solution (1 cc) and shake the mixture for 20 minutes. Acidifyand extract with ether to obtain a product which one dissolves inbenzene and passes through a column of activated Fuller's earth.Evaporate the resulting solution and recrystallize the residue frommethanol to obtain the title product, m.p. 225°-227°; ultravioletabsorption peak at 278 mμ (ε15,300).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 75 13β-Methyl-3-hydroxygona-1,3,5(10), 8-tetraen-17-one

Shake 13β-methyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one (0.05 g)in benzene (25 cc) in hydrogen at atmospheric pressure using a 10%palladized charcoal catalyst (0.025 g). Hydrogenation becomes very slowwhen 1.1 moles hydrogen has been absorbed. Filter and evaporate toobtain the title product (0.035 g), recrystallize from methanol to getpale blue crystals, m.p. 225°-228°, melting to a red liquid; ultravioletabsorption peak at 280 mμ (ε12,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 76 13β-Ethyl-3-hydroxygona-1,3,5(10),8-tetraen-17-one

Hydrogenate 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.5g.) in benzene (25 cc.) at atmospheric pressure using a 10% palladizedcharcoal catalyst (0.025 g.). After the absorption of 1.1 molarequivalents of hydrogen, hydrogenation becomes very slow; remove thecatalyst by filtration and evaporate the filtrate to obtain the titleproduct which crystallizes from methanol in colorless plates (0.35 g.),m.p. 235°-9°; ultra-violet absorption peak at 280.5 mμ (ε 15,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 77 13β-Ethyl-3-acetoxygona-1,3,5(10),8-tetraen-17-one

Hydrogenate 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one (1.8g.) dissolved in benzene (25 ml.) at atmospheric pressure in thepresence of 10% palladized charcoal (100 mg.). After 1.1 molarequivalents of hydrogen has been absorbed (ca. 12hr.) filter off thecatalyst, evaporate the filtrate under reduced pressure andrecrystallize the residue from ethanol. Filter the red product through`Florisil` (60 g.) with benzene-petroleum (3:1), remove the solvent andrecrystallize the product from ethanol to obtain the title product, m.p.132.5°-134.5°; ultra-violet absorption peak at 277 mμ (ε 12,800).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLe 78 13β-Propyl-3-hydroxygona-1,3,5(10),8-tetraen-17-one

Shake 13β-propyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.59 g.)in benzene (30 cc.) with hydrogen at atmospheric pressure in thepresence of a palladized charcoal catalyst (0.3 g.) until the requisiteamount of hydrogen for selective semihydrogenation has been absorbed.Filter the catalyst and evaporate the solvent to obtain greencrystalline material which one recrystallizes from methanol to obtainthe title product (0.36 g.), m.p. 210°-20°, with much decomposition to ared liquid; ultra-violet absorption peak at 281 mμ (ε 11,800).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 79 13β-Methyl-3-acetoxygona-1,3,5(10),8-tetraen-17-one

Hydrogenate 13β-methyl-3-acetoxygona-1,3,5-(10),8,14,-pentaen-17-one((0.05 g., obtained by the acetylation of13β-methyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one using pyridineand acetic anhydride) in benzene (15 cc.) at atmospheric pressure usinga 10% palladized charcoal catalyst (0.025 g.). Hydrogenation slows downmarkedly after the requisite quantity of hydrogen for monohydrogenationhas been absorbed. Remove the catalyst by filtration and evaporate thesolvent, to obtain as residue the crude title product.

This compound has estrogenic acitivity, lowers the blood lipid level,and is useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 80 13β -Methyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17aβ-ol

Add 13β-methyl-3-methoxy-D-homogena-1,3,5(10),8-tetraen-17β-one tosodium borohydride (7 g.) in methanol (400 cc.) and reflux for 30minutes. Acidify the mixture with 50 % aqueous acetic acid and evaporatealmost to dryness. Add water and extract the product with ether. Wash,dry and evaporate the ethereal solution and crystallize the residue fromethanol to obtain the title product, (19 g.), m.p. 83°-6°; ultra-violetabsorption peak at 278 mμ (ε15,800); infrared absorption peaks at 2.96 μand 6.22 μ.

To prepare 7, 13β-dimethyl-3-methoxygona-1,3,5(10),8-tetraen-17β-oltreat 7, 13β-dimethyl-3-methoxygona-1,3,5(10),8,-tetraen-17-one withsodium borohydride according to the manipulative procedure describedabove.

To prepare 13β-methylgona-1,3,5(10), 8-tetraene-3,17β-ol treat13β-methyl-3-hydroxygona-1,3,5(10),8-tetraen-17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13β-ethyl-2,3-dimethoxygona-1,3,5(10),8-tetraen-17β-ol treat13β-ethyl-2,3-dimethoxygona-1,3,5(10),8-tetraen-17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13β-ethyl-3-ethoxygona-1,3,5(10),8-tetraen-17β-ol treat13β-ethyl-3-ethoxygona-1,3,5(10), 8-tetraen-17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13β-isobutyl-3-pentyloxygona-1,3,5(10),8-tetraen-17β-ol treat13β-isobutyl-3-pentyloxygona-1,3,5(10),8-tetraen-17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13β-(3-dimethylaminopropyl)-1,3-dimethoxygona-1,3,5(10),8-tetraen-17β-ol treat13β-(3-dimethylaminopropyl)-1,3-dimethoxygona-1,3,5(10),8-tetraen-17-one with sodium borohydride according to the manipulativeprocedure described above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

EXAMPLE 81 13β-Methyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Add sodium borohydride (0.5 g.) in ethanol (60 cc.) with stirring to13-methyl-3-methoxygona-1,3,5(10), 8-tetraen-17-one (2.0 g.) in ethanol(150 cc.) at 14°-15°. Leave the mixture at room temperature for 1 hour,acidify with glacial acetic acid and evaporate to dryness under reducedpressure. Treat the residue with water, ether-extract and wash and dry.Evaporate the extracts. Recrystallize the residue from a mixture ofmethanol (15 cc.) and water (3 cc.) to obtain the title product (0.90g.), m.p. 110°-2°. A sample sublimes at 110°/10⁻ ⁴ mm. and has anultra-violet absorption peak at 277 mβ (ε 14,500).

C₁₉ H₂₄ O₂ Calculated: C, 80.2%; H, 8.5%. Found: C, 79.3%; H, 8.4%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 82 13β-Ethyl-3-methoxygona-1,3,5(10),8-tetraen-17β -ol

Hydrogenate 13β-ethyl-3-methoxygona-1,3,5(10),8,14-pentaen-17β-ol (0.31g.) and recrystallize the product from hexane-ethyl acetate to obtainthe title product; ultra-violet absorption peak at 280 mμ (ε 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 83 13β-Ethyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Add 13β-ethyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (16.8 g.) to asolution of sodium borohydride (6 g.) in methanol (500 cc.), swirl themixture which boils spontaneously. When all the material has been addedand the reaction has subsided, add acetic acid (15 cc.). Reduce themixture in volume by evaporation of most of the solvent, add water andextract the product with ether. Evaporate the washed and dried extractsto obtain crude crystalline product (16.8 g.), m.p. 102°-5° onrecrystallization from acetonitrile.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds of theinvention.

EXAMPLE 84 13β-Ethyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17aβ-ol

Reduce 13β-ethyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17α-one (20.9g.) exactly as described for the preparation of the 13β-methyl compoundto obtain the title product (20 g.), m.p. 110°-112°; infrared absorptionpeaks at 2.96 μ and 6.23 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 85 13β-Propyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Hydrogenate 13β-propyl-3-methoxygona-1,3,5(10),8,14-pentaen-17β-ol (0.32g.) and recrystallize the product from hexane-ethyl acetate to obtainthe title product; ultra-violet absorption peak at 280mμ (ε15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 86 13β-Propyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Add 13β-propyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (3.5 g.) to asolution of sodium borohydride (1.16 g.) in methanol (120 cc.). Heat thereaction mixture to reflux with stirring for 30 minutes. Concentrate theresulting solution, adjust its pH to 6 with aqueous acetic acid andfilter off the resulting white precipitate which is the title product,(3.1 g.), m.p. 134°-8°; ultra-violet absorption peak at 278 mμ(ε15,350); infrared showed a band due to hydroxyl but no ketone present.

C₂₁ H₂₈ O₂ Calculated: C, 80.7%; H, 9.0%. Found: C, 80.5%; H, 9.0%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 87 13β-Butyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Add sodium borohydride (12.1 g.) to13β-butyl-3-methoxygona-1,3-5(10),8-tetraen-17-one (36.2 g.) in ethanol(1200 cc.) and reflux the mixture for 1 hour. On cooling, acidify themixture with aqueous acetic acid and evaporate to dryness under reducedpressure. Add water to the residue and extract the product with ether.Work up in the usual manner to obtain a residue; recrystallize fromhexane to obtain the 13-n-butyl-title product (26.9 g.) m.p. 90°-100°;ultraviolet absorption peak at 279 mμ (ε15,600); infrared absorptionpeak at 2.88 μ, no absorption in the 5.71-5.88 region.

C₂₂ H₃₀ O₂ Calculated: C, 80.9%; H, 9.3 %. Found: C, 81.0%; H, 9.0%.

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 88 13β-Isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

To a stirred solution of sodium borohydride (6.0 g.) in methanol (500cc. under nitrogen) add13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (17 g.). Gentlyheat the reaction mixture for one minute to initiate the reaction andthen allow to stand for one hour at room temperature. After addingcautiously glacial acetic acid (20 cc.), concentrate the solution invacuo to 1/3 of its volume followed by addition of water. Extract theproduct with ether. Wash the ethereal solution successively with water,sodium bicarbonate, and water, and dry. Evaporate the ether to obtain13β-isobutyl-3-methoxygona-1,3,5(10), 8-tetraen-17β-ol as a gum, (17.0g.; 99%); ultraviolet absorption peak at 278 mμ (ε14,560).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 89 13β -Cetyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Stir a solution of 13β-cetyl-3-methoxygona-1,3,5(10),8-tetraen-17-one(0.60 g.) and sodium borohydride (0.20 g.) in ethanol (110cc.) for 2hours and leave overnight. Reflux with stirring for 2 hours, cool, andadd an excess of 50% aqueous acetic acid. Evaporate the mixture todryness under reduced pressure and partition the residue between etherand water. Work up in the usual manner to get an ether solution of thetitle product as a gum; infrared absorption peak at 3.37 μ (hydroxyl)with no band in the 5.71-5.88 mμ region; ultraviolet absorption peak at278 mμ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 90 13β-Ethylgona-1,3,5(10),8-tetraene-3,17β-diol

Shake 13β-ethylgona-1,3,5-(10),8,14-pentaene-3,17β-diol (0.28 g.) inbenzene (35 cc.) with 10% palladised charcoal (300 mg.) in an atmosphereof hydrogen until 25 cc. of hydrogen has been absorbed. Filter off thecatalyst, evaporate the solvent and recrystallize the residue frommethanol to obtain the title product, m.p. 234°-8°; ultravioletabsorption peak at 280 mμ (ε 41,200).

This compound has estrogenic activity, lowers the blood lipid level andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 91 13β-Propylgona-1,3,5(10),8-tetraene-3,17β-diol

Hydrogenate 13β-propylgona-1,3,5(10),8,14-pentaene-3,17β-diol (0.31 g.)exactly as described in the previous example to obtain the titleproduct, m.p. 210°-218°; ultraviolet absorption peak at 280 mμ(ε12,000),

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 92 13β-Ethyl-3,17β-dimethoxygona-1,3,5(10),8-tetraene

Shake 13β-ethyl-3,17β-dimethoxygona-1,3,5(10),8,14-pentaene (1 g.) in(50 cc.) with 2% palladium on calcium carbonate (0.5 g.) in anatmosphere of hydrogen until 1 molar equivalent of hydrogen (85cc.) hasbeen absorbed. Filter the catalyst and evaporate the solvent to obtainthe title product, m.p. 94°-7°; ultraviolet absorption peak at 278 mμ(ε16,400.).

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 9313β-Ethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraene

Hydrogenate 13β-ethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.0g.) in benzene (70 cc.) at atmospheric pressure using a 5% palladium oncalcium carbonate catalyst (0.70 g.). Uptake of hydrogen ceases after150 cc. has been absorbed. Isolate the product and recrystallize from95% ethanol to obtain the title product (1.3 g.), m.p. 135°-137°;ultraviolet absorption peak at 2.78 mμ (15,100).

C₂₂ H₂₈ O₃ Calculated: C, 77.6%; H, 8.3%. Found: C, 77.5%; H, 8.6%.

This compound possesses estrogenic activity and blood lipid loweringactivity, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

To prepare 6, 13β-dimethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraene hydrogenate6,13β-dimethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaeneusing a 5% palladium on calcium carbonate catalyst according to themanipulative procedure described above.

To prepare13β-ethyl-1,3-dimethoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraenehydrogenate13β-ethyl-1,3-dimethoxy-17,17-ethylenedioxy-gona-1,3,5(10),8,14-pentaeneusing a 5% palladium on calcium carbonate catalyst according to themanipulative procedure described above.

To prepare13β-phenethyl-3-propoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraenehydrogenate13β-phenethyl-3-propoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaeneusing a 5% palladium on calcium carbonate catalyst according to themanipulative procedure described above.

To prepare13β-(3-hydroxypropyl)-3-cyclopentyloxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraenehydrogenate13β-(3-hydroxypropyl)-3-cyclopentyloxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaeneusing a 5% palladium on calcium carbonate catalyst according to themanipulative procedure described above.

These compounds possess estrogenic and blood lipid lowering activity andare useful as intermediates in the preparation of the hormonal compoundsof this invention.

EXAMPLE 9413β-Ethyl-3-methoxy-17,17-(2,2-dimethylpropylenedioxy)-gona-1,3,5,(10),8-tetraene

Shake the 13β-ethyl-3-methoxy-17,17-(2,2-dimethylpropylenedioxy)gona-1,3,5(10), 8,14-pentaene (5 g.) in benzene (75 cc.) containing 2%palladised calcium carbonate (1.75 g.) with hydrogen at atmosphericpressure until one molecular equivalent has been absorbed. Recrystalizethe product from 95% ethanol to obtain the title product; ultravioletabsorption peak at 276.5 mμ (ε13,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 9513β-Propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraene

Shake13β-propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene(2.5 g.) in benzene (80 cc.) with hydrogen at atmospheric pressure inthe presence of a 2% palladium on calcium carbonate catalyst (0.9 g.);hydrogen uptake ceases after the requisite amount (161 cc.) formonohydrogenation has been absorbed. Filter and evaporate to obtain agum, which one crystallizes from ethanol to obtain the title product(1.8 g.), m.p. 119°-120°; ultraviolet absorption peak at 278 mμ(ε15,300).

C₂₃ H₃₀ O₃ Calculated: C, 77.9%; H, 8.5%. Found: C, 77.7%; H, 8.5%.

This compound possesses estrogenic and blood lipid lowering activitiesand is useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 96 13β, 17α-Diethyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol

Shake13β-ethyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-ol (1.9g.) in benzene (100 cc.) with hydrogen at atmospheric pressure in thepresence of a prereduced 2% palladium on calcium carbonate catalyst (0.6g.) until no more hydrogen for selective saturation of the ethynyl grouphas been absorbed. Filter and evaporate the solvent to obtain acrystalline residue which one recrystallizes from methanol, to obtainthe title product (1.5 g.), m.p. 139°-140°; ultraviolet absorption peakat 276 mμ (ε 15,500); infrared absorption peak at 2.79 μ.

To obtain 13β-cetyl-3-methoxy-17β-ethylgona-1,3,5(10), 8-tetraen-17β-olhydrogenate13β-cetyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain 6, 13β-dimethyl-3-methoxy-17α-ethylgona-1,3,5(10),8-tetraen-17β-ol hydrogenate 6,13β-dimethyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain 7,13β-dimethyl-3-methoxy-17α-ethylgona-1,3,5(10),8-tetraen-17.beta.-olhydrogenate 7,13β-dimethyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain 13β,17α-diethyl-2,3-dimethoxygona-1,3,5(10),8-tetraen-17β-olhydrogenate13β-ethyl-2,3-dimethoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain 13β, 17α-diethyl-3-ethoxygona-1,3,5(10),8-tetraen-17β-olhydrogenate13β-ethyl-3-ethoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17β-ol using aprereduced 2% palladium on calcium carbonate catalyst according to themanipulative procedure described above.

To obtain 13β-phenethyl-3-propoxy-17α-ethylgona-1,3,5(10),8-tetraen-17β-ol hydrogenate13β-phenethyl-3-propoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain13β-(3-hydroxypropyl)-3-cyclopentyloxy-17α-ethylgona-1,3,5(10),8-tetraen-17β-olhydrogenate13β-(3-hydroxypropyl)-3-cyclopentyloxy-17α-ethynylgona-1,3,5(10),8-tetraen-17β-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To obtain13β-(2-diethylaminoethyl)-2,3-dimethoxy-17α-ethylgona-1,3,5(10),8-tetraen-17β-olhydrogenate13β-(2-diethylaminoethyl)-2,3-dimethoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17β-olusing a prereduced 2% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

These compounds possess estrogenic activity, and are useful asintermediates in the preparation of the hormonal compounds of thisinvention.

EXAMPLE 97 13β-Propyl-3-methoxy-17α-ethylgona-1,3,5(10),8-tetraen-17β-ol

Shake13β-propyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-ol (1g.) in benzene (100 cc.) with hydrogen at atmospheric pressure in thepresence of a prereduced 2% palladium on calcium carbonate catalyst(0.35 g.). Hydrogenation is interrupted after the requisite amount ofhydrogen for selective saturation of the ethynyl group has beenabsorbed; filter and evaporate to obtain a residue; crystallize frommethanol to obtain the title product (0.5 g.), m.p. 106°-108°;ultraviolet absorption peak at 278 mμ (ε14,700); infrared absorptionpeak at 2.80 μ.

This compound possesses estrogenic activity, and is useful as anintermediate in the preparation of the hormonal compounds of thisinvention.

EXAMPLE 9813β-Butyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17β-ol

Shake13β-butyl-3-methoxy-17α-ethynylgona-1,3,5(10),8-tetraen-17.beta.-ol (3.7g.) in benzene (150 cc.) with hydrogen at atmospheric pressure in thepresence of a prereduced 2% palladium on calcium carbonate catalyst (1.2g.) until the amount of hydrogen required for selective saturation ofthe ethynyl group has been absorbed. Crystallize the red gum (3.7 g.)obtained on filtration and evaporation from methanol to obtain crudeproduct (2.9 g.); a portion is further recrystallized from aqueousacetonitrile to give the pure compound, m.p. 72°-76°; ultravioletabsorption peak at 278 mμ (ε15,600); infrared absorption peak at 2.97 μ.

This compound has estrogenic activity, and is useful in the preparationof the hormonal compounds of this invention.

EXAMPLE 99 -D-Homo-13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17aβ-ol

Add D-homo-13β -ethyl-3-methoxy-gona-1,3,5(10),8-tetraen-17aβ -ol (20g.) in tetrahydrofuran (525 cc.) to liquid ammonia (1500 cc.) andaniline (250 cc.) and add lithium (5 g.) in pieces. After stirring for11/2 hours discharge the blue color by the addition of sodium nitritefollowed by water and isolate the product with ether. Recrystallize theproduct from methanol to obtainD-homo-13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17aβ-ol (15 g.), m.p.103°-105° after previous softening; ultraviolet absorption peak at 280mμ (ε 2,800); infrared absorption peaks at 2.96 and 6.23 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 100 13 β-n-Propyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol

Add 13β-n-propyl-3-methoxy-gona-1,3,5(10),8-tetraen-17β-ol (3.1 g.)dissolved in a mixture of tetrahydrofuran (10 cc.) and freshly distilledaniline (60 cc.) to liquid ammonia (160 cc.) and add lithium metal (1.5g.) in small pieces. Stir the reaction mixture for 3 hours, then quenchwith solid ammonium chloride (12.5 g.) and take up in water.Ether-extract the product and evaporate the washed and dried extracts toobtain a semisolid residue of crude13β-n-propyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (3.1 g.); ultravioletabsorption peak at 279 mμ (ε1,800).

Dissolve the crude material in ether (75 cc.), add heptane (30 cc.) anddistill off the ether, filter the small amount of brown flocculentprecipitate, and finally cool the filtrate to precipitate the purifiedproduct as an off-white solid (2.3 g.), m.p. 141°-143° C.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 101 13-n-Butyl-3-methoxygona-1,3,5(10)-trien-17β-ol

To 13 -n-butyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol (0.8 g.) inaniline (20 cc.) and tetrahydrofuran (10 cc.) add liquid ammonia (100cc.), followed by sodium (0.8 g.) in small pieces during 5 minutes whilestirring the mixture. After a further 15 minutes stirring, discharge theblue color with solid ammonium chloride. Work up the product with etherin the usual way, and evaporate the resulting ether solution to leave asresidue a gum; take this up in hot methanol (10 cc.), filter a littleinsoluble material and allow the solution to stand for 12 hours at 0° C.Crystals of 13-n-butyl-3-methoxygona-1,3,5(10)-trien-17β-ol aredeposited and filtered off (0.6 g.), m.p. 123°-125° C after previoussoftening and a little melting at 60°-70° C.; ultraviolet absorptionpeak at 278 mμ (ε2,100); infrared absorption peaks at 2.86-2.97 (broadband), 6.21, 7.94, 9.62 μ.

This compound possesses estrogenic and blood lipid lowering activitiesand is useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 102 13β-Isobutyl-3-methoxygona-1,3,5(10)-trien-17β-ol

Add a solution of 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol(17.0 g.) in dry tetrahydrofuran (125 cc.; distilled) slowly to amixture of liquid ammonia (680 cc., distilled), aniline (85 cc.,distilled) and tetrahydrofuran (125 cc.) with stirring. Then add lithium(7.9 g.) in small portions. After the addition of lithium is completed,stir the blue mixture for another 3 hours. Discharge the blue color bythe cautious addition of ammonium chloride followed by warm (50°) water.Extract the crude product with benzene. Wash the extracts with water,hydrochloric acid, (20%) sodium bicarbonate, water and dry. Evaporatethe solvent in vacuo to obtain a gum which on crystallization fromether-petroleum ether gives13β-isobutyl-3-methoxygona-1,3,5(10)-trien-17β-ol (13.0 g.; 76%); m.p.103°-104° C.: ultraviolet absorption peak at 2.78 mμ (ε 1,975); infraredabsorption peak at 2.83 μ.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 103 13β-Ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol

To 13β-ethyl-3-methoxy-gona-1,3,5(10), 8-tetraen-17β-ol (16.8 g.)dissolved in a mixture of aniline (150 cc.) and tetrahydrofuran (50 cc.)add liquid ammonia (400 cc.). Add lithium metal (6.0 g.) gradually insmall pieces during 10 minutes, and stir the blue suspension obtained.After 2 hours, add ammonium chloride (50 g.) to the reaction mixtureuntil a clear solution is obtained; then add water (600 cc.) andether-extract the mixture. Evaporate the washed and dried extracts toobtain as residue a crystalline solid. Recrystallize from hexane (300cc.), to obtain 13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (14 g.),m.p. 126°-30°.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

To obtain 13β-cetyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol treat13β-cetyl-3-methoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithium andaniline in liquid ammonia according to the manipulative proceduredescribed above.

To obtain 7,13β-dimethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol treat7,13β-dimethyl-3-methoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithiumand aniline in liquid ammonia according to the manipulative proceduredescribed above.

To obtain 13β-ethyl-2,3-dimethoxy-gona-1,3,5(10)-trien-17β-ol treat13β-ethyl-2,3-dimethoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithium andaniline in liquid ammonia according to the manipulative proceduredescribed above.

To obtain 13β-ethyl-1,3-dimethoxy-gona-1,3,5(10)-trien-17β-ol treat13β-ethyl-1,3-dimethoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithium andaniline in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-ethyl-3-ethoxy-gona-1,3,5(10)-trien-17β-ol treat13β-ethyl-3-ethoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithium andaniline in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-phenethyl-3-propoxy-gona-1,3,5(10)-trien-17β-ol treat13β-phenethyl-3-propoxy-gona-1,3,5(10),8-tetraen-17β-ol with lithium andaniline in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-isobutyl-3-pentyloxy-gona-1,3,5(10)-trien-17β-ol treat13β-isobutyl-3-pentyloxy-gona-1,3,5(10),8-tetraen-17β-ol with lithiumand aniline in liquid ammonia according to the manipulative proceduredescribed above.

To prepare13β-(3-hydroxypropyl)-3-cyclopentyloxy-gona-1,3,5(10)-trien-17β-ol treat13β-(3-hydroxypropyl)-3-cyclopentyloxy-gona-1,3,5(10),8-tetraen-17.beta.-olwith lithium and aniline in liquid ammonia according to the manipulativeprocedure described above.

To obtain 13β-(3-dimethylaminopropyl)-3-methoxy-gona-1,3,5(10),8-trien-17β-ol treat13β-(3-dimethylaminopropyl)-3-methoxy-gona-1,3,5(10), 8-tetraen-17β-olwith lithium and aniline in liquid ammonia according to the manipulativeprocedure described above.

These compounds possess estrogenic and blood lipid lowering activity andare useful as intermediates for preparing the hormonal compounds of thisinvention.

EXAMPLE 104 13β, 17α-Diethyl-3-methoxygona-1,3,5(10)-trien-17β-ol

Shake 13β-ethyl-3-methoxy-17α-ethylgona-1,3,5(10),9-tetraen-17β-ol (0.3g.) in ethanol (10 cc.) with 10% palladised charcoal (0.3 g.) in anatmosphere of hydrogen until uptake ceases (25 cc. absorbed). Filter thecatalyst and remove the solvent and recrystallize the residue fromethanol to obtain 13β, 17α-diethyl-3-methoxygona-1,3,5(10)-trien-17β-ol(0.11 g.), m.p. 160°-161°.

This compound has estrogenic activity, and is useful as an intermediatefor preparing the hormonal compounds of this invention.

EXAMPLE 105 13β-Methyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ-ol

Add 13β-methyl-3-methoxy-D-homogona-1,3,5(10)-trien-17aβ-ol (13 g.) intetrahydrofuran (300 cc.) to liquid ammonia (650 cc.) followed by theaddition of lithium (4.3 g.). After stirring for 30 minutes add absoluteethanol dropwise over a period of 1 hour to discharge the blue color.Precipitate the product with water, filter and dry to give13β-methyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ-ol, m.p. 148°-155°;infrared absorption peaks at 2.98 μ, 5.88 μ and 5.98 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 106 13β-Ethyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ-ol

Substitute 13β-ethyl-3-methoxy-D-homogona-1,3,5(10)-trien-17aβ-ol for13β-methyl-3-methoxy-D-homogona-1,3,5(10)-trien-17aβ-ol to give13β-ethyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ-ol; m.p. 135°-138°;infrared absorption peaks at 3.03, 5.92, 6.01 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 107 13β-Ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol

Add 13β-Ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) intetrahydrofuran (50 cc.) to stirred liquid ammonia (150 cc.), followedby lithium foil (0.5 g.) and then add ethanol (6 cc.) during 20 minutes.When the blue color is discharged, add water and work up the productwith ether, to yield 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol as asolid (0.47 g.).

To prepare 13β-ethyl-2,3-dimethoxy-gona-2,5(10)-dien-17β-ol react13β-ethyl-2,3-dimethoxy-gona-1,3,5(10) -trien-17β-ol in tetrahydrofuranwith lithium in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-ethyl-1,3-dimethoxy-gona-1(10), 3-dien-17β-ol react13β-ethyl-1,3-dimethoxy-gona-1,3,5,(10)-trien-17β-ol in tetrahydrofuranwith lithium in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-ethyl-3-ethoxy-gona-2,5(10)-dien-17β-ol react13β-ethyl-3-ethoxy-gona-1,3,5(10)-trien-17β-ol in tetrahydrofuran withlithium in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-phenethyl-3-n-propoxy-gona-2,5(10)-dien-17β-ol react13β-phenethyl-3-n-propoxy-gona-1,3,5(10)-trien-17β-ol in tetrahydrofuranwith lithium in liquid ammonia according to the manipulative proceduredescribed above.

To prepare isobutyl-3-n-pentoxy-gona-2,5(10)-dien-17β-ol react13β-isobutyl-3-n-pentoxy-gona-1,3,5(10)-trien-17β-ol in tetrahydrofuranwith lithium in liquid ammonia according to the manipulative proceduredescribed above.

To prepare 13β-(3-hydroxypropyl)-3-cyclopentoxy-gona-2,5(10)-dien-17β-olreact 13β-(3-hydroxypropyl)-3-cyclopentoxy-gona-1,3,5(10)-trien-17β-olin tetrahydrofuran with lithium in liquid ammonia according to themanipulative procedure described above.

To prepare13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10),3-dien-17β-ol react13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1,3,5(10)-trien17.beta.-ol in tetrahydrofuran with lithium in liquid ammonia accordingto the manipulative procedure described above.

These compounds have estrogenic acitivty, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

EXAMPLE 108 13β-Ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol

To 13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (1.0 g.) in1-methoxypropan-2-ol (100 cc.) add liquid ammonia (200 cc.), followed bylithium metal (1.2 g.) in small pieces with stirring. After discharge ofthe blue color add an excess of ammonium chloride, followed by water;filter off the crude 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol anddry, m.p. 98°-104°. No selective ultra-violet absorption beyond 220 mμ;infrared absorption peaks at 3.03, 5.92, 6.01 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 109 13β-n-Propyl-3-methoxy-gona-2,5(10)-dien-17β-ol

Dissolve 13β-n-propyl-3-methoxy-gona-1,3,5(10)-dien-17β-ol in a mixtureof freshly distilled pyrrole (50 cc.) and liquid ammonia (100 cc. ) andthen add lithium (1.0 g.) in small pieces as quickly as the productionof foam permits. When the blue color is discharged, add excess ammoniumchloride, followed by water (100 cc.) Extract the product into ether,wash, dry and evaporate. Recrystallize the residue (0.9 g.), frommethanol, to give 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.65g.), m.p. 153°-6°; no selective ultra-violet absorption beyond 220 mμ;infrared absorption peaks at 2.91, 5.90, 6.04 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 110 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol

Add liquid ammonia (100 cc.) to13β-isopropyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) intetrahydrofuran (50 cc.) followed by lithium metal (0.5 g.), and stirthe solution for 10 minutes. Then add ethanol (6 cc.) dropwise. When theblue color is discharged, add water and extract the product with ether.Evaporate the washed and dried extracts to give crude 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.5 g.) as colorless gum.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 111 13β-n-Butyl-3-methoxy-gona-2,5(10)-dien-17β-ol

Add 13β-n-butyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in amixture of tetrahydrofuran (5 cc.) and ether (15 cc.) dropwise to astirred solution of lithium (0.5 g.) in liquid ammonia (60 cc.). After 5minutes beyond completion of addition, add ethanol (8 cc.) dropwise andwhen the blue color is discharged, add water and extract the mixturewith ether. Work up in the usual way to give13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol as a crystalline solid,m.p. 135°-9°; infrared absorption peaks at 2.97, 6.25, 6.38 and 8.16 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 112 13β-Ethyl-3-ethoxy-gona-2,5(10)-dien-17β-ol

Heat under reflux 13β-ethyl-3-hydroxy-gona-1,3,5(10)-trien-17β-ol (1.75g.) and potassium carbonate (3 g.) for six hours with ethanol (40 cc.)and ethyl iodide (20 cc.) in a nitrogen atmosphere. Then concentrate thesolution to half its original volume, add water and take the product upin ether. Wash, dry and evaporate the ethereal solution andrecyrstallize the residue from hexane to give13β-ethyl-3-ethoxy-gona-1,3,5(10)-trien-17β-ol. Add this product (0.5g.), tetrahydrofuran (50 cc.) to liquid ammonia (100 cc.) and addlithium (0.5 g.). After stirring for 10 minutes add a mixture of ethanol(6 cc.) and tetrahydrofuran (10 cc.) over a period of 20 minutes, andwhen the blue color is discharged add water and extract the mixture withether. Wash, dry and evaporate the ethereal solution and recrystallizethe residue from ethanol to give13β-ethyl-3-ethoxy-gona-2,5(10)-dien-17β-ol. No selective ultra-violetabsorption beyond 220 mμ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 113 13β-Ethyl-3-n-propoxy-gona-2,5(10)-dien-17β-ol

Use n-propyl iodide (20 cc.) instead of ethyl iodide and proceed exactlyas described for the 3-ethoxy compound to give13β-ethyl-3-n-propoxy-gona-2,5(10)-dien-17β-ol; no selectiveultra-violet absorption beyond 220 mμ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 114 13β-Methyl-3-methoxy-D-homo-gona-2,5(10)-dien-17a-one

Reflux 13β-methyl-3-methoxy-D-homo-gona-2,5(10)-dien-17aβ-ol (4 g.)under nitrogen in toluene (130 cc.) containing cyclohexanone (40 cc.)and aluminum isopropylate (1.8 g.) for 3 hours. Cool, add water (40 cc.)followed by anhydrous sodium sulphate (40 g.) and filter the mixture.Evaporate the filtrate to dryness, first at 30°/20 mm. then at 50°/0.1mm. to afford 13β-methyl-3-methoxy-D-homo-gona-2,5(10)-dien-17a-one.Infrared absorption peaks at 5.85, 5.92, 6.01 μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 115 13β-Ethyl-3-methoxy-D-homo-gona-2,5(10)-dien-17a-one

Reflux 13β-ethyl-3-methoxy-D-homo-gona-2,5(10)-dien-17aβ-ol (10 g.) withaluminum isopropylate (8 g.) in dry toluene (450 cc.) and drycyclohexanone (140 cc.) for 4 hours in an atmosphere of nitrogen.Decompose the cooled solution with water (ca. 25 cc.) and dry by theaddition of sodium sulphate. Filter the mixture and remove the solventsfirst at 20 mm. Hg. and then at 90° 0.2 mm. Hg. Dry the residue overphosphorus pentoxide in a desiccator to give13β-ethyl-3-methoxy-D-homo-gona-2,5(10)-dien-17a-one (11.1 g.), m.p.138°-145° C; infrared absorption peaks at 5.88, 6μ.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 116 13β-Ethyl-3-methoxy-gona-2,5(10)-dien-17-one

Reflux a mixture of 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.8g.), aluminium isopropoxide (0.36 g.), toluene (26 cc.) andcyclohexanone (8 cc.) under nitrogen for 3 hours. Allow the solution tocool under nitrogen, add water (5 cc.) and shake the mixture vigorously.Add anhydrous sodium sulphate (5 g.), shake the mixture again, and thenallow to stand for 30 minutes. Filter the solution, combine the filtratewith ether-washings of the residue, and evaporate, first at 30°/20 mm.,then at 50°/0.1 mm. to leave as a crystalline solid13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one; infrared absorption peaksat 5.78, 5.92, 6.01 μ, with no absorption due to hydroxyl.

To prepare 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one react13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17-one react13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17-one react13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-ethyl-3-ethoxy-gona-2,5(10)-dien-17-one react13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-ethyl-3-n-propoxy-gona-2,5(10)-dien-17-one react13β-ethyl-3-n-propoxy-gona-2,5(10) -dien-17β-ol intoluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-ethyl-2,3-dimethoxy-gona-2,5(10)-dien-17-one react13β-ethyl-2,3-dimethoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-ethyl-1,3-dimethoxy-gona-1(10),3-dien-17-one react13β-ethyl-1,3-dimethoxy-gona-1(10),3-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-phenethyl-3-n-propoxy-gona-2,5(10)-dien-17-one react13β-phenethyl-3-n-propoxy-gona-2,5(10)-dien-17β-ol intoluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-isobutyl-3-n-pentoxy-gona-2,5(10)-dien-17-one react13β-isobutyl-3-n-pentoxy-gona-2,5(10)-dien-17β-ol in toluene withcyclohexanone and aluminium isopropoxide according to the manipulativeprocedure described above.

To prepare 13β-(3-hydroxypropyl)-3-cyclopentoxy-gona-2,5(10)-dien-17-onereact 13β-(3-hydroxypropyl)-3-cyclopentoxy-gona-2,5(10)-dien-17β-ol intoluene with cyclohexanone and aluminium isopropoxide according to themanipulative procedure described above.

To prepare 13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10),3-dien-17-one react13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10),3-dien-17β-olintoluene with cyclohexanone and aluminium isopropoxide according to themanipulative procedure described above.

These compounds have estrogenic activity and are useful as intermediatesin the preparation of the hormonal compounds of the invention.

EXAMPLE 117 13β-n-Propyl-3-methoxy-gona-2,5(10)-dien-17-one

Reflux 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (3.0 g.) withaluminium isopropoxide in toluene and cyclohexanone according to theconditions of Oppenauer oxidation. Isolate and recrystallize the productfrom methanol to give 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one(2.0 g.), m.p. 128°-31° C. with softening at 125°.

C₂₁ H₃₀ O₂ Calculated: C, 80.2 H, 9.6%. Found: C, 80.0 H, 9.55%.

This compound has estrogenic activity and is useful as an intermediatefor preparing the hormonal compounds of this invention.

EXAMPLE 118 13β-n-Butyl-3-methoxy-gona-2,5(10)-dien-17-one

Reflux 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (8 g.) in toluene(450 cc.) containing cyclohexanone (120 cc.) and aluminium isopropoxide(5 g.) under nitrogen for 4 hours. Cool, and add water (15 cc.)dropwise, followed by anhydrous sodium sulphate. Filter the mixture,wash the residue with ether and combine the filtrate and washings, dryand evaporate finally at 90°/1.05 mm. to give13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17-one (6.0 g.), m.p. 124°-128°,(from methanol); infrared absorption peaks at 5.80, 6.02 μ.

This compound has estrogenic activity, and is useful as an intermediatefor preparing the hormonal compounds of this invention.

EXAMPLE 11913β-Methyl-3-methoxy-17aα-ethynyl-D-homo-gona-2,5(10)-dien-17a.beta.-ol

Add a solution of 13β-methyl-3-methoxy-D-homo-gona-2,5(10) diene-17a-one(6.5 g.) in dimethylacetamide (50 cc.) to a stirred suspension oflithium acetylide (4.25 g.) in dioxane (25 cc.), ethylene diamine (1cc.), and dimethylacetamide (25 cc.) in an atmosphere of acetylene.After stirring for 20 hours pour the mixture onto crushed ice (150 g.)and extract with benzene. Wash, dry and evaporate the extracts andrecrystallize the residue from ethanol to give 13β-methyl-3-methoxy-17aα-ethynyl-D-homo-gona-2,5(10)-dien-17aβ-ol; infrared absorption peaks at2.88, 3.05, 5.90, 6.01 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 12013β-Ethyl-3-methoxy-17aα-ethynyl-D-homo-gona-2,5(10)-dien-17a.beta.-ol

Dissolve 13β-ethyl-3-methoxy-D-homo-gona-2,5(10)-diene-17-one (8.8 g.)in dimethylacetamide (70 cc.) and add a suspension of lithium acetylide(10 g.) in ethylenediamine-dioxan (1:1; 60 cc.). Then pass acetyleneover the surface of the stirred mixture for 15 hours. Decompose thereaction mixture by pouring onto ice, collect the product in ether andevaporate the washed, dried ether solution to give13β-ethyl-3-methoxy-17aα-ethynyl-D-homo-gona-2,5(10)-diene17a.beta.-ol;m.p. 118-124° (7 g.) 74%. Infrared absorption peaks at 2.85, 3.06, 5.90,6.0 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 121 13β-Ethyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien17β-ol

Add a suspension of lithium aluminum acetylide (obtained by passingexcess acetylene through a solution of lithium aluminum hydride (2.0g.). in tetrahydrofuran (25 cc.) with stirring to13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (0.6 g.) in tetrahydrofuran(5 cc.). After standing for 18 hours, add ether (40 cc.) followed by thecareful dropwise addition of water until effervescence ceases. Addanhydrous magnesium sulphate (10 g.) and filter the solution andevaporate the filtrate under reduced pressure to give13β-ethyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol (0.6 g.).Infrared absorption peaks at 2.80, 3.05, 4.59, 6.00 μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 122 13β-Ethyl-3-methoxy-17α-propynyl-gona-2,5(10)-dien-17β-ol

Add 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (10 g.) to a solutionof propynyl magnesium bromide (prepared from magnesium (6 g.) and ethylbromide (25 g.) in tetrahydrofuran (500 cc.) and propyne). Stir themixture for 6 hours under reflux, cool and decompose the water (100cc.). Add "Celite", filter the resultant sludge and wash the residuethoroughly with ether. Separate the organic phase in the filtrate, wash,dry and evaporate. Reflux the product in methanol for 20 minutes, cooland filter to give 13β-ethyl-3-methoxy-17α-propynyl-gona-2,5(10)-dien-17β-ol (9.5 g.), m.p. 158°-61° after softening at 144°; infraredabsorption peaks at 2.90, 3.08, 4.50, 5.88, 6.00 μ; no selectiveultra-violet absorption beyond 220 m.sub.μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 123 13β-Ethyl-3-methoxy-17α-allyl-gona-2,5(10)-dien-17β-ol

Dissolve 13β-ethyl-3-methoxy-gona-2,5(10) -dien-17-one intetrahydrofuran (100 cc.) and allyl bromide (11.5 g.), and add thesolution dropwise to a refluxing suspension of magnesium (1 g.) in allylbromide (0.6 g.) and tetrahydrofuran (50 cc.). Allow the mixture toreflux for 6 hours, and then add water (100 cc.) to the cooled solutionfollowed by enough "Celite" to make a thick paste. Filter the mixture,wash the residue thoroughly with ether and separate the organic phasefrom the filtrate, wash, dry and evaporate the ether solution andcrystallize the residue from methanol to give 13β-ethyl-3-methoxy-17α-allyl-gona-2,5(10) dien-17β-ol (3.8 g.); infrared absorption peaks at3.03, 5.88, 6.01, 6.10 μ; no selective ultraviolet absorption beyond 220m.sub.μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 123 13β-Ethyl-3-methoxy-17α-allyl-gona-2,5(10)-dien-17β-ol

Dissolve 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one in tetrahydrofuran(100 cc.) and allyl bromide (11.5 g.), and add the solution dropwise toa refluxing suspension of magnesium (1 g.) in allyl bromide (0.6 g.) andtetrahydrofuran (50 cc.). Allow the mixture to reflux for 6 hours, andthen add water (100 cc.) to the cooled solution followed by enough"Celite" to make a thick paste. Filter the mixture, wash the residuethoroughly with ether and separate the organic phase from the filtrate,wash, dry and evaporate the ether solution and crystallize the residuefrom methanol to give 13β-ethyl-3-methoxy-17 α-allyl-gona-2,5(10)-dien-17β-ol (3.8 g.); infrared absorption peaks at 3.03, 5.88,6.01, 6.10 μ; no selective ultraviolet absorption beyond 220 mμ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 12413β-Ethyl-3-methoxy-17α-(2-isobutenyl)-gona-2,5(10)-dien-17.beta.-ol

Add a suspension of 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (4 g.)in ether (500 cc.) and methallyl chloride (8 g.) to a Grignard solution,prepared from methallyl chloride (8 g.) and magnesium (20 g.) in ether(100 cc.), at such a rate that gentle reflux is maintained. Reflux themixture for 4 hours and then decompose the cooled solution with water(ca. 100 cc). Add "Celite", filter the resultant pasty mass and wash theresidue thoroughly with ether. Separate the organic phase from thefiltrate, wash, dry and evaporate, and recrystallize the residue frommethanol to give13β-ethyl-3-methoxy-17α-(2-isobutenyl)gona-2,5(10)-dien-17.beta.-ol (4g.). Infrared absorption peaks at 2.86, 5.88, 6.01, 6.10 μ; no selectiveultraviolet absorption beyond 220 mμ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 125 13β-n-Propyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol

Add a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (1.74g.) in dry tetrahydrofuran (25 cc.) slowly to a stirred suspension ofacetylene dimagnesium bromide (from magnesium, 0.36 g.) intetrahydrofuran. After completion of the reaction decompose the Grignardcomplex with saturated ammonium chloride solution (100 cc.) and work upthe product by means of ethyl acetate, purify by chromatography onneutral alumina, and recrystallize from methanol to give13β-n-propyl-3-methoxy-17α-ethynyl-gona2,5(10)-dien-17β-ol (0.33 g.),m.p. 91-6° (deomp.); infrared absorption peaks at 3.77, 3.03, 5.88, 5.99μ (a hydroxyl, a methine group and a dihydroanisole system).

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 126 13β-n-Propyl-3-methoxy-17α-allyl-gona-2,5(10)-dien-17β-ol

Warm allyl bromide (4.5 cc.) with magnesium turnings (107 g.) in ether(40 cc.) and then add 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (2g.) in ether (70 cc. ) containing allyl bromide (2.5 cc.) slowly withstirring. Reflux the mixture with stirring for 3 hours, and to thecooled mixture add aqueous sodium potassium tartrate and extract theproduct with ether. Wash, dry and evaporate the extracts to give aresidue which is mainly13β-n-propyl-3-methoxy-17α-allyl-gona-2,5(10)-dien-17β-ol.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 127 13β-n-Propyl-3-methoxy-17α-propynyl-gona-2,5(10)-dien-17β-ol

Add a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (7.5g.) in tetrahydrofuran (250 cc.) with stirring under nitrogen topropynyl magnesium bromide (from ethyl magnesium bromide 39 g. andpropyne in tetrahydrofuran (500 cc.). Reflux the mixture with stirringfor 3 hours, and on cooling add saturated aqueous ammonium chloride (120cc.) and extract the product obtained from the washed, dry extracts withether. Dissolve the residue in boiling methanol and store for 18 hoursat -10°. Filter off the crystalline deposit to yield13β-n-propyl-3-methoxy-17α-propynylgona-2,5(10)-dien-17-β-ol (6.9 g.),m.p. 104°-111°.

To prepare 13β-n-propyl-3-methoxy-17α-methyl-gona-2,5(10)-dien-17β-oltreat 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one with methylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β-isobutyl-3-methoxy-17α-ethyl-gona-2,5(10) -dien-17β-oltreat 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17-one with ethylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β-isobutyl-3-methoxy-17α-methyl-gona-2,5(10)-dien-17β-oltreat 13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17-one with methylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β,17α-di-ethyl-3-ethoxy-gona-2,5(10)-dien-17β-ol treat13β-ethyl-3-ethoxy-gona-2,5(10)-dien-17-one with ethyl magnesium bromideaccording to the manipulative procedure described above.

To prepare 13β-ethyl-3-n-propoxy-17α-methyl-gona-2,5(10)-dien-17β-oltreat 13β-ethyl- 3-n-propoxy-gona-2,5(10)-dien-17-one with methylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β, 17α-diethyl-2,3-dimethoxy-gona-2,5(10)-dien-17β-ol treat13β-ethyl-2,3-dimethoxy-gona-2,5(10)-dien-17-one with ethyl magnesiumbromide according to the manipulative procedure described above.

To prepare 13β-ethyl-1,3-dimethoxy-17α-methyl-gona-1(10),3-dien-17β-oltreat 13β-ethyl-1,3-dimethoxy-gona-1(10),3-dien-17-one with methylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β-phenethyl-3-n-propoxy-17α-ethyl-gona-2,5(10)-dien-17β-oltreat 13β-phenethyl-3-n-propoxy-gona-2,5(10)-dien- 17-one with ethylmagnesium bromide according to the manipulative procedure describedabove.

To prepare 13β-isobutyl-3-n-pentoxy-17α-methyl-gona-2,5(10)-dien-17β-oltreat 13β-isobutyl-3-n-pentoxy-gona-2,5(10)-dien-17-one with methylmagnesium bromide according to the manipulative procedure describedabove.

To prepare13β-(3-hydroxypropyl)-3-cyclopentoxy-17α-ethyl-gona-2,5-(10)-dien-17β-oltreat 13β-(3-hydroxypropyl)-3-cyclopentoxy-gona-2,5(10)-dien-17-one withethyl magnesium bromide according to the manipulative proceduredescribed above.

To prepare13β-(3-dimethylaminopropyl)-1,3-dimethoxy-17α-methyl-gona-1(10),3-dien-17β-ol treat13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10), 3-dien-17-one withmethyl magnesium bromide according to the manipulative proceduredescribed above.

These compounds are useful as intermediates for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 12813β-n-Propyl-3-methoxy-17α-(1-methallyl)-gona-2,5(10)-dien-17.beta.-ol

Add a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (3.1g.) in ether (130 cc.) with stirring under nitrogen to crotyl magnesiumbromide (from crotyl bromide, 13.5 g., and magnesium, 9.7 g.) in ether.Reflux the mixture for 4 hours, and leave at room temperature overnight.Add saturated aqueous ammonium chloride (70 cc.) and extract the productwith ether. Wash, dry and evaporate the extracts to yield13β-n-propyl-3-methoxy-17α-(1-methallyl)-gona-2,5(10)-dien-17.beta.-ol;infrared absorption peak at 11.0μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 12913β-n-Propyl-3-methoxy-17α-(2-methallyl)-gona-2,5(10)-dien-17.beta.-ol

Employ the method of the previous example but react13β-n-propyl-3-methoxygona-2,5(10)-dien-17-one (3.66 g. with 2-methallylmagnesium chloride (from the metal, 8.76 g. and 2-methallyl chloride,10.9 g.). Purify the crude product by extraction with boiling methanolto afford a residue of13β-n-propyl-3-methoxy-17α-(2-methallyl)-gona-2,5(10)-dien-17.beta.-ol(3.87 g.), m.p. 135-140°; infrared absorption peaks at 2.87, 5.90, 6.00,6.09 .sub.μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 130 13β-n-Butyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol

Add a solution of 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17-one (2 g.)in dimethylacetamide (200 cc.) slowly to a suspension of lithium carbide(2.5 g.) in dimethylacetamide (50 cc.) at 0° in an atmosphere ofnitrogen. Stir the mixture at room temperature for 48 hours, cool to 0°and decompose by the dropwise addition of water (100 cc.). Add water andextract with ether to give after removal of the solvent,13β-n-butyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol (1.8 g.) as agum; infrared absorption peaks at 2.95, 3.05, 5.90, 5.99 .sub.μ.

This compound is useful as an intermediate for preparing the novelcompositions of this invention which have hormonal activity.

EXAMPLE 131 13β-Methyl-D-homo-17a -hydroxy-gon-4-en-3-one

Add 13β-methyl-D-homo-3-methoxy-gona-2,5(10)-dien-17a -ol (0.7 g.) indioxane (20 cc.) with stirring to methanol (20 cc.) containing 11Nhydrochloric acid (2.7 cc.) and water (1 cc.). Continue stirring for 2hours, add water and extract the mixture with ether. Evaporate thewashed and dried extracts, dissolve the residue in benzene andchromatograph on Florex to give 13β-methyl-D-homo-17a-hydroxy-gon-4-en-3-one; ultra-violet absorption peak at 242 m₈₂ (ε17,000); infrared absorption peaks at 3.03, 5.92, 6.01 .sub.μ.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 132 13β-Ethyl-D-homo-17a -hydroxy-gon-4-en-3-one

Substitute 13β-ethyl-D-homo-3-methoxy-gona-2,5(10)-dien-17a -ol for13β-methyl-D-homo-3-methoxy-gona-2,5(10)-dien-17a -ol to give13β-ethyl-D-homo-17a -hydroxy-gon-4-en-3-one; ultra-violet absorptionpeak at 242m.sub.μ (ε17,000); infrared absorption peaks at 3.03, 5.92,6.01 .sub.μ.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 133 13β-Ethyl-17β-hydroxy-gon-4-en-3-one

Add 13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in 100 ml.of tetrahydrofuran to 150 ml. of liquid ammonia, followed by 0.5 g. oflithium foil, and stir the mixture for 10 minutes. Add ethanol (6 ml.)and tetrahydrofuran (10 ml.) over a period of 20 minutes. Afterdisappearance of the blue color add water, extract the mixture well withether and evaporate the washed and dried ether extract. Dissolve thecrystalline residue in 50 ml. of methanol and reflux for 30 minutes with30 ml. of 3N HCL. Remove most of the methanol under reduced pressure,and extract the residue with ether. Chromatograph the ether extract onalumina. Use benzene-ether (1:1) to elute13-β-ethyl-17β-hydroxy-gon-4-en-3-one; m.p. 152°-55° C.

C₁₉ H₂₈ O₂ Calculated: C, 79.1% H, 9.8%. Found: C, 79.25% H, 9.65%.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 134 13β-Ethyl-17β-hydroxy-gon-4-en-3-one

Dissolve 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.47 g.) in hotmethanol (25 cc.). Add 3N hydrochloric acid (15 cc.) and keep themixture at 70° C. under nitrogen for 1 hour. Add water and work up withether and chromatograph the resulting gum on activated alumina (40 g.).Elute with ether to give a fraction (0.2 g.) which on recrystallizationfrom light petroleum gives 13β-ethyl-17β-hydroxy-gon-4-en-3-one; m.p.153-5° C; ultra-violet absorption peak at 240 m.sub.μ (ε 16,300).

C₁₉ H₂₆ O₂ Calculated: C, 79.1% H, 9.8%. Found: C,79.2% H, 9.7%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 135 13β-Ethyl-17β-hydroxy-gon-4-en-3-one

Add to 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (1.0 g.) in methanol(50 cc.), 3N hydrochloric acid (20 cc.); shake the mixture for 2 hours,pour into water, and extract the product with ether. Work up in theusual way and take up the resulting gum in benzene and chromatograph onneutral alumina. Elute with ether to give a crystalline material andrecrystallize from a mixture of ether and pentane to yield13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.5 g.), m.p. 144°-7°;ultra-violet absorption peak at 240 m.sub.μ (ε15,500); infraredabsorption peaks at 2.94, 6.06, 6.23 .sub.μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

To prepare 13β-cetyl-17β-hydroxy-gon-4-en-3-one treat13β-cetyl-3-methoxy-gona-2,5(10)dien-17β-ol with methanolic hydrochloricacid according to the manipulative procedure described above.

To prepare 13β-ethyl-2-methoxy-17β-hydroxy-gon-4-en-3-one treat13β-ethyl-2,3-dimethoxy-gona-2,5(10)-diene-17β-ol with methanolichydrochloric acid according to the manipulative procedure describedabove.

To prepare 13β-phenethyl-17β-hydroxy-gon-4-en-3-one treat13β-phenethyl-3-methoxy-gona-2,5(10)-diene-17β-ol with methanolichydrochloric acid according to the manipulative procedure describedabove.

To prepare 13β-(3-hydroxypropyl)-17β-hydroxy-gon-4-en-3-one treat13β-(3-hydroxypropyl)-3-methoxy-gona-2,5(10)-diene-17β-ol withmethanolic hydrochloric acid according to the manipulative proceduredescribed above.

To prepare 13β-(3-dimethylaminopropyl)-1-oxo-17β-hydroxygonan-3-onetreat13β-(3-dimethylaminopropyl)-1,3-dimethoxy-gona-1(10),3-diene-17β-ol withmethanolic hydrochloric acid according to the manipulative proceduredescribed above.

These compounds possess androgenic and anabolic activity and are usefulas an intermediate for preparing the hormonal compounds of thisinvention.

EXAMPLE 136 13β-Ethyl-17β-hydroxy-gon-4en-3-one

Stir 13β-ethyl-17β-hydroxy-gon-5(10)-en-3-one (300 mg.) for 2 hoursunder nitrogen at room temperature with methanol (10 cc.)-11Nhydrochloric acid (0.5 cc.)-water (0.3 cc.). Add sodium bicarbonate (2g.) and ether (50cc.), filter the mixture, evaporate the ether andrecrystallize the residue from ethyl acetate-ether to give13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.2 g.), m.p. 147°-149°;ultraviolet absorption peak at 242 m.sub.μ (ε 17,600); infraredabsorption peaks at 2.78, 2.90, 6.02, 6.17.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 137 13β-Ethyl-17β-hydroxy-gon-4-en-3-one

Add sodium borohydride (200 mg.) in ethanol (25 cc.) to13β-ethylgon-4-en-3,17-dione (1 g.) in ethanol (50 cc.) at 8°. After 15minutes add an excess of acetic acid and evaporate the solution todryness under reduced pressure. Add water, collect the product in ether,and after this work up in the usual manner, recrystallize from a mixtureof ether and pentane to obtain 13β-ethyl-17β-hydroxy-gon-4-en-3-one;ultraviolet absorption peak at 240 m.sub.μ (ε 15,500); infraredabsorption peaks at 2.94, 6.06, 6.23.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 138 13β-n-Propyl-17β-hydroxy-gon-4-en-3-one

Add 3N hydrochloric acid (1 cc.) to a solution of13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.61 g.) in boilingmethanol (70 cc.) and cool the mixture immediately and allow to standfor 4 1/2 hours. Pour the product into water (300 cc.) and extract themixture with ether; work up in the usual way to give as residue anamorphous solid (0.6 g.). Crystallize this solid from a mixture of etherand hexane. Take up the resulting solid in benzene (20 cc.) andchromatograph on a column of neutral alumina. Elute the product withether and recrystallize from a mixture of ether and hexane to obtain13β-n-propyl-17β-hydroxy-gon-4-en-3-one (0.08 g.), mp. 126°-7°;ultraviolet absorption peak at 240 m.sub.μ (ε 15,000); infraredabsorption peaks at 2.92, 6.01, 6.20 μ. Evaporation of the motherliquors gives a second, polymorphic, form of the same substance (0.17g.), m.p. 144°-5°, having ultraviolet and infrared spectra identicalwith the first material; a mixture of the two forms has m.p. 144°-5°.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 139 13β-n-Propyl-17β-hydroxy-gon-4-en-3-one

By substituting an equivalent amount of 13β-n-propyl-17β-hydroxy gon-5(10)-en-3-one for 13β-ethyl-17β-hydroxy-gon-5(10)-en-3-one in example136, there is obtained 13β-n-propyl-17β-hydroxy-gon-4-en-3-one; infraredabsorption peaks at 2.92, 6.01, 6.20 .sub.μ ; ultraviolet peak at 240m.sub.μ (ε15,000).

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 140 13β-Isopropyl-17β-hydroxy-gon-4-en-3-one

Dissolve 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol in methanol(36 cc.), concentrated hydrochloric acid (2.4 cc.) and water (1.6 cc.)and allow the mixture to stand at room temperature for 2 hours. Addwater and collect the product in ether. Wash, dry and evaporate theethereal solution and chromatograph the residue on alumina (30 g.).Elute with benzene containing 30% ether and evaporate the solvent toobtain 13β-isopropyl-17β-hydroxy-gon-4-en-3-one as a gum; infraredabsorption peak at 5.99 μ; ultraviolet absorption peak at 249 m.sub.μ(ε12,000).

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 141 13β-n-Butyl-17β-hydroxy-gon-4-en-3-one

Shake 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.49 g.) withconcentrated hydrochloric acid (1.2 cc.) in water (0.8 cc.) and methanol(18 cc.) until solution is complete. Allow to stand 2 hours at roomtemperature, pour the mixture into water and extract the product withether. Evaporate the washed and dried ether extracts and recrystallizethe solid from a mixture of ethyl acetate and ether to obtain the titlecompound (0.32 g.), m.p. 169°-70°; ultraviolet absorption peak at 240m.sub.μ (ε17,000); infrared absorption peaks at 2.92, 6.01 .sub.μ.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 142 13β -Isobutyl-17β-hydroxy-gon-4-en-3-one

Add to a mixture of concentrated hydrochloric acid (4.8 cc.), water (3.2cc.) and methanol (.72 cc. )13β-isobutyl-3-methoxy-gona-2,5(10)-dien-17β-ol (2.0 g.). Heat theresulting solution on a steam bath for 30 minutes with stirring. Cool toroom temperature, dilute the solution with water (160 cc.) and extractwith ether. Wash the ethereal solution with water, sodium bicarbonate,and water, dry over anhydrous sodium sulfate. Filter and remove thesolvent under reduced pressure to give a gum. Recrystallize from ethylacetate to obtain the title compound (0.8 g., 43%, m.p. 124.0°-125.5°;ultraviolet absorption peak at 240 m.sub.μ (ε18,200).

C₂₁ H₃₂ O₂ Calculated: C, 79.7%; H, 10.2%. Found : C, 79.5%, H, 10.0%.

This compound has estrogen antagonistic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 143 13β, 17α-Diethyl-17β-hydroxy-gon-4-en-3-one

Dissolve 13β, 17α-diethyl-gon-5-en-3, 17β-diol (0.1 g.) in acetone(30cc.) and add a few pieces of solid carbon dioxide. Add 8N-chromicacid dropwise until the color of the solution remains reddish orange (3drops) and then add isopropanol (1 cc.). Shake the mixture for 5 minuteswith 10% aqueous sodium hydroxide (50 cc.) and then add benzene (30 cc.)and remove the organic layer. Wash the organic layer thoroughly withbrine and dry over Na₂ SO₄. Remove the solvent and triturate the residuewith ether to give a crystalline precipitate. Recrystallize from etherto obtain the title compound, m.p, 138°-142° undepressed on admixturewith authentic material.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 144 13β-Ethyl-17β-methoxy-gon-4-en-3-one

Add 13β-ethyl-3, 17β-dimethoxy-gona-2,5(10)-diene (0.8 g.) intetrahydrofuran (5 cc.) to methanol (72 cc.) in an atmosphere ofnitrogen and add a mixture of hydrochloric acid (4.8 cc.) and water (3.2cc.). Add a further 10 cc. of tetrahydrofuran and after 1 hour dilutethe solution with water and extract with ether. Wash, dry and evaporatethe ethereal extracts and chromatograph the residue on neutral alumina.Remove impurities by elution with benzene. Wash the column with ether,evaporate the eluate and recrystallize the residue from hexane to obtainthe title compound (0.2 g.), m.p. 117-119°; ultraviolet absorption λmax. 240 m.sub.μ (ε15,800); infrared spectrum (KBr disc) 6.0, 6.2, 8.8,9.05 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 145 13β-Ethyl-gon-4-en-3,17-dione

Add 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (12.9 g.) with stirringunder nitrogen to methanol (300 cc.) containing 11N hydrochloric acid(20 cc) and water (13 cc.). Stir two hours and add sodium bicarbonate(21 g.) portionwise. Filter the mixture and evaporate the filtrate todryness. Recrystallize the residue from ethyl acetate (75 cc.) to obtainthe title compound (10 g.), m.p. 158-161° C; ultraviolet absorption peakat 240 m.sub.μ (ε17,800); infrared absorption peaks at 5.78, 6.00, 6.17.sub.μ.

C₁₉ H₂₆ O₂ Calculated: C, 79.76%; H, 9.15%; Found : C, 80.0%; H, 9.0%.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 146 13β-Ethyl-gon-4-en-3,17-dione

Add 13β-ethyl-gon-5(10)-en-3,17 -dione (1 g.) with stirring undernitrogen to methanol (25 cc.) containing 11N hydrochloric acid (1.75cc.) and water (1.1 cc.). Stir for 2 hours, add sodium bicarbonate (1.75g.) and filter the mixture. Evaporate the filtrate to dryness andrecrystallize the residue from ethyl acetate to obtain the titlecompound; ultraviolet absorption peak at 240 m.sub.μ (ε 17,800);infrared absorption peaks at 5.78, 6.00, 6.17 .sub.μ.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 147 13β-Ethyl-gon-4-en-3,17-dione

Heat 13β-ethyl-3-methoxy-17,17-ethylenedioxy-gona-2,5(10)-diene (0.1 g.)in glacial acetic acid (2.5 cc.) and water (1 cc.) on a steam bath for20 minutes, bring finally to boiling and allow to cool. Add aqueoussodium bicarbonate to neturalize the solution and ether extract theproduct. Wash, dry and evaporate the ether extracts to furnish a residue(0.065 g.); crystallize from a mixture of acetone and light petroleum toobtain the title compound (0.01 g.), m.p. 154°-5°; ultravioletabsorption peak at 239 m.sub.μ (ε15,000); infrared absorption peaks at5.75, 5.96 .sub.μ.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 148 13β-Methyl-D-homo-17aβ-(3-phenylpropionoxy)-gon-4-en-3-one

Add 3-phenylpropionyl chloride (1 cc.) in benzene (3 cc.) to13β-methyl-D-homo-17aβ -hydroxy-gon-4-en-3-one (1 g.) in pyridine (3.5cc.) at -20°. Keep the mixture overnight at -10°, add crushed ice andextract the mixture with ether-benzene (1:1). Wash the extracts in turnwith 2N aqueous potassium hydroxide, water, 2N hydrochloric acid, andbrine, and dry. Evaporate the solvent to give a residue. Dissolve theresidue in benzene and chromatograph on silica gel to obtain the titlecompound: infrared absorption peaks at 5.80, 5.99 μ.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 149 13β-Ethyl-D-homo-17aβ-(3-phenylpropionoxy)-gon-4-en-3-one

Substitution of 13β-ethyl-D-homo-17aβhydroxy-gon-4-en-3-one for13β-methyl-D-homo-17aβhydroxy-gon-4-en-3-one in the preceding examplegives the title compound; infrared absorption peaks at 5.78, 5.99 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 150 13β-Ethyl-17β-acetoxy-gon-4-en-3-one

Add acetyl chloride (1 cc.) in benzene 95 cc.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.5 g.) in pyridine (5 cc.) at -20°.Keep the mixture at -10° for 18 hours, work up and recrystallize theproduct from methanol to obtain the title compound (0.9 g.); ultravioletabsorption peak at 240 mμ (ε16,700); infrared absorption peaks at 5.75,5.99 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

To prepare 13β-ethyl-17β-propionoxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with propionyl chloride accordingto the manipulative procedure described above.

To prepare 13β-ethyl-17β-hexanoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with hexanoyl chloride according tothe manipulative procedure described above.

To prepare 13β-ethyl-17β-heptanoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with heptanoyl chloride accordingto the manipulative procedure described above.

To prepare 13β-ethyl-17β-octanoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with octanoyl chloride according tothe manipulative procedure described above.

To prepare 13β-ethyl-17β-lauroyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with lauroyl chloride according tothe manipulative procedure described above.

To prepare 13β-ethyl-17β-myristoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with myristoyl chloride accordingto the manipulative procedure described above.

To prepare 13β-ethyl-17β-palmitoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with palmitoyl chloride accordingto the manipulative procedure described above.

To prepare 13β-ethyl-17β-oleoyloxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with oleoyl chloride according tothe manipulative procedure described above.

To prepare 13β-ethyl-17β-cyclohexylacetoxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with cyclohexylacetyl chlorideaccording to the manipulative procedure described above.

To prepare 13β-ethyl-17β-2-phenylpropionoxy-gon-4-en-3-one treat13β-ethyl-17β-hydroxy-gon-4-en-3-one with 2-phenylpropionyl chlorideaccording to the manipulative procedure described above.

EXAMPLE 151 13β-Ethyl-17β-isovaleroyloxy-gon-4-en-3-one

Keep 13β-ethyl-17β-hydroxy-gon-4-en-3-one (6 g.) with isovaleroylchloride (7.2 g.) in pyridine at room temperature for 20 hours. Addaqueous sodium bicarbonate and extract the product with ether. Wash, dryand evaporate the extracts and purify the residue by chromatography uponneutral alumina. Distill at 200°-230°/.01 mm. and crystallize fromhexane to obtain the title compound, m.p. 82°- 89°; ultravioletabsorption peak at 240 mμ (ε15,650); infrared absorption peaks at 5.76,5.99, 6.18 μ.

C₂₄ H₃₆ O₃ Calculated: C, 77.4%; H, 9.7%. Found: C, 77.1%; H, 9.7%.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 152 13β-Ethyl-17β-decanoyloxy-gon-4-en-3-one

Add decanoyl chloride (1.9 g.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one(1.3 g.) in pyridine (12.5 cc.) and allow the mixture to stand at roomtemperature overnight. Pour the mixture in 2N hydrochloric acid andextract with ether. Wash, dry and evaporate the extracts andrecrystallize the residue from benzene-hexane to give the title compound(1.0 g.), m.p. 97°-97.5°; ultraviolet absorption peak at 239 mμ(ε16,500); infrared absorption peaks at 5.74, 5.99, 6.17 μ.

C₂₉ H₄₆ O₃ Calculated: C, 78.7%; H, 10.5%. Found: C, 78.7%; H. 10.5%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 153 13β-Ethyl-17β-(undec-10-enoyloxy)-gon-4-en-3-one

Add undec-10-enoyl chloride (2 g.) in benzene (6 cc.) to13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°.Keep the mixture at -10° for 17 hours, add to water and extract withbenzene. Wash, dry and evaporate the extracts and recrystallize theresidue from methanol to obtain the title compound, m.p. 87°-88°;ultraviolet absorption peak at 240 mμ (ε17,000); infrared absorptionpeaks at 5.79, 6.00, 6.20 μ.

C₃₀ H₄₆ O₃ Calculated: C, 79.2%; H, 10.2%. Found: C, 79.0%; H, 10.0%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 154 13β-Ethyl-17β-(3-cyclopentylpropionoxy)-gon-4-en-3-one

Add 3-cyclopentylpropionyl chloride (2 g.) in benzene (6 cc.) to13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (6 cc.) at -15°.Keep the mixture at -10° for 17 hours, work up and recrystallize theproduct from methanol to give the title compound, m.p. 88°- 89°;ultraviolet absorption peak at 241 mμ (ε17,000); infrared absorptionpeaks at 5.80, 6.00, 6.18 μ.

C₂₇ H₃₉ O₃ Calculated: C, 78.8%; H, 9.55%. Found: C, 78.5%; H, 9.65%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 155 13β-Ethyl-17β-hemisuccinoyloxy-gon-4-en-3-one

Reflux 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.5 g.) with succinicanhydride (1.0 g.) in pyridine (10 cc.) for 2 hours. Cool the mixtureand pour into an excess of 4N hydrochloric acid and extract the mixturewith ether-chloroform. Wash the extract with 2N HCl, dilute with etherand exhaustively extract with aqueous sodium bicarbonate. Acidify thebicarbonate extracts and extract the product with chloroform.Recrystallize it twice from chloroform-ether to obtain the titlecompound, (0.8 g.), m.p. 179°-182°; ultraviolet absorption peak at 239mμ (ε15,600); infrared absorption peaks at 5.81, 6.02, 8.13 μ.

C₂₃ H₃₂ O₅ Calculated: C, 71.1%; H, 8.3%. Found: C, 71.0%; H, 8.2%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 156 13β-Ethyl-17β-benzoyloxy-gon-4-en-3-one

Treat 13β-ethyl-17β-hydroxy-gon-4-en-3-one (2 g.) in pyridine (20 cc.)with benzoyl chloride (3 cc.) in benzene (10 cc.) at -10°. Keep themixture at that temperature for 18 hours and then pour into 2Nhydrochloric acid (200 cc.). Extract the product with ether and wash,dry and evaporate the extracts. Triturate the residue with a mixture ofether and hexane. Filter the crystalline material obtained and dissolvein benzene and purify by chromatography on neutral alumina.Recrystallize from a mixture of ethyl acetate and hexane to give thetitle compound, m.p. 141°-9°; ultraviolet light absorption peak at 237mμ (ε27,300).

C₂₆ H₃₂ O₃ Calculated: C, 79.55%; H, 8.2%. Found: C, 79.3%; H, 8.0%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 157 17β-Ethyl-17β-phenylacetoxy-gon-4-en-3-one

Add phenylacetyl chloride (1.5 cc.) in benzene (4.5 cc.) to13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.5 g.) in pyridine (5 cc.) at-18°. Keep the mixture at -10° for 16 hours, add ice-water and extractthe product with ether. Wash, dry and evaporate the extracts to aresidue and chromatograph on neutral alumina to obtain a crystallineproduct and recrystallize from methanol to obtain the title compound,m.p. 143°-145°; ultraviolet absorption peak at 240 mμ (ε16,300);infrared absorption peaks at 5.75, 6.00 μ.

This compound has androgenic and anabolic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 158 13β-Ethyl-17β-(3-phenylpropionoxy)-gon-4-en-3-one

Add 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.11 g.) in dry pyridine (0.35cc.) at -20° to 3-phenylpropionyl chloride (0.11 g.) in benzene (0.3cc.). Keep this at -10° for 16 hours, add ice-cold water and extractwith a mixture of equal volumes of ether and benzene. Wash the extractsin turn with 2N potassium hydroxide solution, water, 2N hydrochloricacid solution, and brine, and dry. Evaporate solvent to give a residueand recrystallize from a mixture of ether and ethyl acetate to obtainthe title compound (0.10 g.), m.p. 135°-40°; infrared absorption peaksat 5.81, 5.99, 8.51, 13.3, 14.3 μ, showing no absorption due tohydroxyl.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 159 13β-Ethyl-17β-nicotinoyloxy-gon-4-en-3-one

Reflux 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1 g.) with nicotinicanhydride (2 g.) in pyridine (20 cc.) for 3 hours. Cool, add water,evaporate the mixture to dryness and extract with benzene. Wash, dry andevaporate the extracts to a residue and recrystallize from methanol toobtain the title compound; ultraviolet absorption peak at 239 mμ(ε20,000); infrared absorption peaks at 5.81, 6.00, 6.28 μ.

C₂₅ H₃₁ NO₃ Calculated: C, 76.3%; H, 7.9%; N, 3.6%. Found: C, 76.1%; H,7.9%; N, 3.7%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 160 13β-Propyl-17β-benzyloxy-gon-4-en-3-one

Esterify 13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) with benzoylchloride (2.0 g.). Purify the product by chromatography on Florex andrecrystallize from ethyl acetate to obtain the title compound, m.p.198°-200°; ultraviolet absorption peak at 240 mμ (ε25,000); infraredabsorption peaks at 5.84, 6.00 μ.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 161 13β-Propyl-17β-(3-phenylpropionoxy)-gon-4-en-3-one

Add 3-phenylpropionyl chloride (2.9 g.) in benzene (10 cc.) to13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) in pyridine at -10°. Pourthe mixture into ice water and extract with benzene-ether. Wash, dry andevaporate the extracts to a gum and purify by chromatography uponFlorex. Recrystallize from ethyl acetate-hexane to obtain the titlecompound, m.p. 104°-108°. Ultraviolet absorption peak at 240 mμ(ε16,000); infrared absorption peaks at 5.76, 6.00 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 162 13β-Butyl-17β-(3-phenylpropionoxy)-gon-4-en-3-one

Cool 13β-butyl-17β-hydroxy-gon-4-en-3-one (0.10 g.) in pyridine (0.3cc.) to -20° and add 3-phenylpropionyl chloride (0.10 g.) in benzene(0.3 cc.). Stir the mixture at -10° for 16 hours, add ice-cold water,ether (15 cc.) and benzene (15 cc.). Separate the organic layers andwash in turn with 2N sodium hydroxide solution, water and brine, anddry. Evaporate the solvent to an uncrystallizable gum, and take up in alittle benzene and filter through neutral alumina (5 g.), then wash withmore benzene. Evaporate the resulting benzene solution to obtain thetitle compound as a gum (0.085 g.); infrared absorption peaks at 5.78,5.99, 13.3, 14.3 μ, with no absorption due to hydroxyl.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 163 13β-Isobutyl-17β-(3-phenylpropionoxy)-gon-4-en-3-one

Add 3-phenylpropionyl chloride (0.5 g.) in benzene (1.5 cc.) withswirling to 13β-isobutyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) in pyridine(2 cc.) at -20°. Store the mixture at -10° for 18 hours, add water andextract the product with ether. Wash, dry and evaporate the extracts togive a residue and recrystallize from methanol to give the titlecompound, m.p. 101°-106°; ultraviolet absorption peak at 240 mμ(ε15,300); infrared absorption peaks at 5.75, 5.95 μ.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 164 13β-Ethyl-3,3-ethylenedithio-gon-4-en-17β-ol

Treat 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.47 g.) in methanol (5 cc.)and ethanedithiol (0.25 cc.) with boron trifluoride etherate (0.25 cc.).Allow the mixture to stand at room temperature for 15 minutes, cool to0°, filter the precipitate and wash with cold methanol to obtain thetitle compound, (0.38 g.), m.p. 167°-169°.

C₂₁ H₃₂ OS₂ Calculated: C, 69.2%; H, 8.85%. Found: C, 69.1%; H, 8.9%.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 165 13β-Methyl-D-homo-17aα-ethynyl-17aβ-hydroxy-gon-4-en-3-one

Add 13β-methyl-D-homo-3-methoxy-17aα-ethynyl-gona-2,5(10)-diene-17aβ-ol(0.7 g.) in dioxane (20 cc.) with stirring to methanol (20 cc.)containing 11N hydrochloric acid (2.8 cc.) and water (1.6 cc.). Stir atroom temperature for 2 hours, add water and extract the mixture withether. Evaporate the washed and dried extracts to give a residue anddissolve in benzene and chromatograph on Florex to obtain the titlecompound; infrared absorption peaks at 2.97, 3.03, 6.02 μ.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 166 13β-Methyl-D-homo-17aα-ethyl-17aβ-hydroxy-gon-4-en-3-one

Add13β-methyl-D-homo-3-methoxy-17aα-ethyl-gona-2,5(10)-diene-17a.beta.-ol(0.6 g.) in dioxane (20 cc.) with stirring to methanol (20 cc.)containing 11N hydrochloric acid (2.4 cc.) and water (1.6 cc.). Stir for2 hours at room temperature, add water and extract the mixture withether. Wash, dry and evaporate the extracts to give a residue andrecrystallize from ethyl acetate to obtain the title compound; ultraviolet absorption peak at 240 mμ (ε15,000); infrared absorption peaks at2.86, 6.01 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 167 13β-Ethyl-D-homo-17aα-ethynyl-17aβ-hydroxy-gon-4-en-3-one

Dissolve13β-ethyl-D-homo-3-methoxy-17aα-ethynyl-gona-2,5(10)-diene-17a.beta.-ol(3.5 g.) in methanol (180 cc.) containing hydrochloric acid (12 cc.) andwater (8 cc.). After 2 hours at room temperature add water and extractthe mixture with ether. Wash, dry and evaporate the organic extract andrecrystallize the residue from ethyl acetate to obtain the titlecompound 1.95 g., m.p. 171°-4°. Ultra violet absorption peak at 240 mμ(ε17,400); infrared absorption peaks at 2.99, 3.1, 6.03 μ.

C₂₂ H₃₀ O₂ Calculated: C, 80.94%; H, 9.26%. Found: C, 80.73%; H, 9.35%.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 168 13β,17aα-Diethyl-17aβ-hydroxy-D-homo-gon-4-en-3-one

Dissolve 13β,17aα-diethyl-3-methoxy-D-homo-gona-2,5(10)-dien-17aβ-ol(3.5 g.) in methanol (135 cc.) containing water (6 cc.) and hydrochloricacid (9 cc.). Stir the mixture for 1 hour and then pour into brine andextract with ether. Evaporate the washed and dried ether extracts andrecrystallize the residue from acetone-hexane to obtain the titlecompound 2.225 g., m.p. 153°-155°. Ultra violet absorption peak at 240mμ (ε16,320); infrared absorption peaks at 2.92, 6.03 μ.

C₂₂ H₃₄ O₂ Calculated: C, 79.95%; H, 10.36%. Found: C, 79.93%; H,10.34%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 169 13β-Ethyl-17α-methyl-17β-hydroxy-gon-4-en-3-one

Heat a solution of13β-ethyl-3-methoxy-17α-methyl-gona-2,5(10)-dien-17β-ol (0.5 g.) inmethanol (55 cc.) under nitrogen to boiling and add 3N hydrochloric acid(0.6 cc.). Allow the solution to cool to room temperature and keep undernitrogen for 3 hours; then add water and extract the mixture with ether.Evaporate the washed and dried extracts and recrystallize the residuefrom a mixture of ether and hexane, and subsequently from benzene, toyield the title compound as a benzene solvate. Remove the benzene bydrying at 100° for 7 hours to obtain the free compound (0.2 g.), m.p.128°-9°. Ultraviolet absorption peak at 240 mμ (ε16,200). Infraredabsorption peaks at 2.95, 6.01 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 170 13β-Ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one

To 13β-ethyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol (0.7 g.) inmethanol (36 cc.) add water (1.6 cc.) and concentrated hydrochloric acid(2.4 cc.). After standing at room temperature for 2 hours, add ether andevaporate the washed and dried ethereal solution to yield a gum.Dissolve the gum in benzene (5 cc.) and absorb the solution on anactivated Fuller's earth (50 g.). Elute with light petroleum containingincreasing proportions of benzene to yield a crystalline by-product;then elute with benzene containing a small proportion of ether to yielda crystalline product. Recrystallise the latter from ethyl acetate, toobtain the title compound (0.11 g.), m.p. 203°-6°; infrared absorptionpeaks at 2.97, 3.03, 6.02 μ.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 171 13β-Ethyl-17α-vinyl-17β-hydroxy-gon-4-en-3-one

Shake 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) inpyridine (20 cc.) containing a 2% palladium-calcium carbonate catalyst(150 mg.) with hydrogen at atmospheric pressure until one molecularequivalent of hydrogen has been absorbed. Recrystallise the producttwice from ether-hexane and dry for 4 hours at 65°/0.005 mm. to yieldthe title compound, m.p. 108°-111°; ultraviolet absorption peak at 240(ε15,200); infrared absorption peak at 10.9μ.

C₂₁ H₃₀ O₂ Calculated: C, 80.2%; H, 9.6%. Found: C, 80.4%; H, 9.7%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 172 13β,17α-Diethyl-17β-hydroxy-gon-4-en-3-one

Add 13β,17α-diethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.29 g.) to 15cc. of a solution prepared by mixing concentrated hydrochloric acid (2.4cc.), water (1.6 cc.) and methanol (36 cc.). Shake the mixture for 10minutes, during which time the solid dissolves. After 2 hours pour thesolution into water (50 cc.) and extract the mixture with ether. Wash,dry and evaporate the extracts and recrystallise the residue (0.255 g.)from a mixture of ethyl acetate and light petroleum, to yield the titlecompound (0.196 g.), m.p. 139°-41°. Ultraviolet absorption peak at 240mμ (ε15,000). Infrared absorption peaks at 2.86, 6.01 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 173 13β-Ethyl-17α-propynyl-17β-hydroxy-gon-4-en-3-one

Suspend 13β-ethyl-3-methoxy-17α-propynyl-gona-2,5(10)-dien-17β-ol inmethanol (36 cc.) and stir with concentrated hydrochloric acid (2.4cc.), water (1.6 cc.) and dioxane (10 cc.) until dissolution iscomplete, and then for a further 20 minutes. Precipitate the product bythe addition of water, filter, wash and dry. Recrystallise from ethylacetate-hexane to yield the title compound, m.p. 124°-5°; infraredabsorption peaks at 3.03, 4.55, 6.02 μ; ultraviolet absorption peak at240 mμ (ε15,600).

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 174 13β-Ethyl-17α-(2-propenyl)-17β-hydroxy-gon-4-en-3-one

Suspend 13β-ethyl-3-methoxy-17α-(2-propenyl)-gona-2,5(10)-dien-17β-ol inmethanol (72 cc.), concentrated hydrochloric acid (4.8 cc.) and water(3.2 cc.) in an atmosphere of nitrogen. Add dioxane (20 cc.) and stirthe mixture until dissolution is complete, and then for a further 20minutes. Add water and extract the mixture with ether. Wash the etherealsolution with saturated sodium bicarbonate solution and water, and dry.Evaporate the solvent to obtain the title compound; infrared absorptionpeaks at 2.94, 6.02, 6.19 μ. Ultraviolet absorption peak at 240 mμ(ε15,600).

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 175 13β-Ethyl-17α-n-propyl-17β-hydroxy-gon-4-en-3-one

Keep a solution of13β-ethyl-3-methoxy-17α-n-propyl-gona-2,5(10)-dien-17β-ol (0.53 g.) in amixture of methanol (22.5 cc.), 12N hydrochloric acid (1.5 cc.), andwater (1.5 cc.) under nitrogen for 21/2 hours at room temperature. Thenadd ice-water (75 cc.), filter off the precipitated solid and dissolvein ether (50 cc.); wash, dry and evaporate the ether solution, to yielda solid residue. Recrystallise the residue repeatedly from ethylacetate, to obtain the title compound (0.23 g.), m.p. 132°-4.5°.Ultraviolet absorption peak at 240 mμ (ε15,900); infrared absorptionpeaks at 2.92, 6.02, 6.18 μ.

C₇₉ H₃₄ O₂ Calculated: C, 79.5%; H, 10.4%. Found: C, 79.8%; H, 10.2%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 176 13β-Ethyl-17α-(2-isobutenyl)-17β-hydroxy-gon-4-en-3-one

Suspend13β-ethyl-3-methoxy-17α-(2-isobutenyl)-gona-2,5(10)-dien-17.beta.-ol(1.5 g.) in methanol (36 cc.), concentrated hydrochloric acid (2.4 cc.),water (1.6 cc.) and dioxane (10 cc.). When the material has dissolved,add water, filter the precipitate and again stir with methanol (36 cc.),concentrated hydrochloric acid (2.4 cc.) and water (1.66 cc.) for 20minutes. Then gradually add water and filter the precipitate; wash withwater, dry and crystallise from ethyl acetate-hexane and then fromacetonitrile to yield the title compound (2 g.); infrared absorptionpeaks at 2.90, 6.01, 6.20, 11.3 μ; ultraviolet absorption peak at 240 mμ(ε16,800).

This compound has estrogen antagonistic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 177 13β-n-Propyl-17α-methyl-17β-hydroxy-gon-4-en-3-one

Shake 13β-n-propyl-3-methoxy-17α-methyl-gona-2,5(10)-dien-17β-ol (1.0g.) with 44 cc. of an aqueous methanolic hydrochloric acid solution andstir for 2 hours; then pour the product into water and work up withether. Purify by chromatography on silica gel (elute with ether), andrecrystallise from a mixture of ethyl acetate and hexane to obtain thetitle compound (0.35 g.), m.p. 134°-5.5°; ultraviolet absorption peak at240 mμ (ε18,100); infrared absorption peak at 6.02 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 178 13β-n-Propyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one

Shake 13β-n-propyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol (0.31g.) with a solution prepared by mixing concentrated hydrochloric acid(0.81 cc.), water (0.54 cc.) and methanol (12.15 cc.), until the soliddissolves. After addition of water, work up with ether, purify byrecrystallization from cyclohexane to obtain the title compound (0.1g.), m.p. 149°-50.5°; ultraviolet absorption peak at 240 mμ (ε15,700);infrared absorption peaks at 2.99, 3.06, 6.04, 6.16 μ.

C₂₂ H₃₀ O₂ Calculated: C, 80.9%; H, 9.3%. Found: C, 81.0%; H, 9.31%.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 179 13β-n-Propyl-17α-vinyl-17β-hydroxy-gon-4-en-3-one

Hydrogenate 13β-n-propyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (0.5 g.)to yield the title compound (.425 g.), m.p. 94°-97°; ultravioletabsorption peak at 240 mμ (ε15,600); infrared absorption peak at 10.9 μ.

C₂₂ H₃₂ O₂ Calculated: C, 80.4%; H, 9.8%; Found: C, 81.1%; H, 9.9%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 180 13β-n-Propyl-17α-ethyl-17β-hydroxy-gon-4-en-3-one

Stir a mixture of13β-n-propyl-3-methoxy-17α-ethyl-gona-2,5(10)-dien-17β-ol (0.8 g.) intetrahydrofuran (20 cc.), methanol (50 cc.), 12N hydrochloric acid (3.3cc.) and water (2.2 cc.) at room temperature for 21/2 hours and thenpour into sodium chloride solution; extract the mixture with ether andwash, dry and evaporate the extracts. Dissolve the crystalline residueobtained (0.8 g.) in a mixture (25 cc.) of equal volumes of benzene andhexane and chromatograph on silica gel; elute with a mixture of equalvolumes of benzene and chloroform to yield a crystalline material.Recrystallise this product from a mixture of benzene and lightpetroleum, to give a benzene solvate, m.p. 93°-5°; and thenrecrystallise this material from a mixture of hexane and ethyl acetateto obtain the solvent free product,13β-n-propyl-17α-ethyl-17β-hydroxy-gon-4-en-3-one (0.2 g.), m.p.98°-100°; ultraviolet absorption peak at 240 mμ (ε15,700 ); infraredabsorption peaks at 2.92, 6.02, 6.18 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 181 13β-n-Propyl-17α-propynyl-17β-hydroxy-gon-4-en-3-one

Stir 13β-n-propyl-3-methoxy-17α-propynyl-gona-2,5(10)-dien-17β-ol (2.5g.) under nitrogen with methanol (135 cc.) containing 11N hydrochloricacid (9 cc.) and water (6 cc.). After two hours add isopropyl alcohol(35 cc.) and continue stirring for a further 30 minutes. Add the mixtureto brine and extract the product with ether. Evaporate the washed anddry extracts to a glass, dissolve in benzene and chromatograph onFlorex. Elute with benzene containing 5% ether and recrystallise theproduct so obtained from ethyl acetate-hexane to yield the titlecompound, m.p. 182- 184°; ultraviolet absorption peak at 240 mμ(ε16,700).

C₂₃ H₃₂ O₂ Calculated: C, 81.1%; H, 9.5%. Found: C, 80.95%; H, 9.4%

This compound has progestational and estrogen antagonistic activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

EXAMPLE 182 13β-n-Propyl-17α-allyl-17β-hydroxy-gon-4-en-3-one

Stir 13β-n-propyl-3-methoxy-17α-allyl-gona-2,5(10)-dien-17β-ol (0.77 g.)under nitrogen in isopropyl alcohol (25 cc.) containing 11N hydrochloricacid (2.5 cc.) and water (1.6 cc.) for 2.5 hours. Filter the mixture,add to brine and extract the product with ether. Evaporate the washedand dry extracts and purify the residue by chromatography on Florex andby recrystallisation from ethyl acetate to obtain the title compound,m.p. 135°-137°; ultraviolet absorption peak at 241.5 mμ (ε17,500);infrared absorption peaks at 2.95, 6.02, 6.18 μ.

C₂₃ H₃₄ O₂ Calculated: C, 80.65%; H, 10.0%.

Found: C, 80.4%; H, 9.8%.

This compound has progestational anabolic and androgenic activity and isuseful as an intermediate for preparing the hormonal compounds of thisinvention.

EXAMPLE 183 13β,17α-Di-n-propyl-17β-hydroxy-gon-4-en-3-one

Stir 13β,17α-di-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (1.07 g.)under nitrogen in methanol (50 cc.) containing water (2.5 cc.) and 11Nhydrochloric acid (3.5 cc.) at room temperature for 2 hours. Then addwater and extract the product with ether. Evaporate the washed and dryextracts and purify the residue by chromatography on alumina, byrepeated recrystallization from ethyl acetate, and by sublimation at145°/.003 mm. to obtain the title compound, (.34 g.), m.p. 147°-49°.Ultraviolet absorption peak at 241.5 mμ (ε16,600); infrared absorptionpeaks at 2.91, 6.02, 6.19 μ.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 184 13β-n-Propyl-17α-(1-methallyl)-17β-hydroxy-gon-4-en-3-one

Stir13β-n-propyl-3-methoxy-17α-(1-methallyl)-gona-2,5(10)-dien-17.beta.-ol(1.5 g.) under nitrogen with methanol (90 cc.) containing 11Nhydrochloric acid (9 cc.) and water (6 cc.). Add the mixture to brineand extract the product with ether. Evaporate the washed and driedextracts to yield the title compound; ultraviolet absorption peak at 240mμ (ε13,500); infrared absorption peak at 11.0 μ.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 185 13β-n-Propyl-17α-(2-methallyl)-17β-hydroxy-gon-4-en-3-one

Employ the method of Example 184 to hydrolyse13β-n-propyl-3-methoxy-17α-(2-methallyl)-gona-2,5(10)-dien-17.beta.-ol.Purify the product by chromatography on Florex and recrystallisationfrom ethyl acetate to afford the title compound, m.p. 141.5°-143.5°;ultraviolet absorption peak at 241 mμ (ε16,700); infrared absorptionpeaks at 2.87, 6.01, 6.18 μ.

C₂₄ H₃₆ O₂ Calculated: C, 80.85%; H, 10.2%. Found: C, 80.8%, H, 9.9%.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 186 13β-n-Butyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one

Hydrolyse 13β-n-butyl-3-methoxy-17α-ethynyl-gona-2,5(10)-dien-17β-ol (2g.) by the method of Example 184 and purify the product bychromatography on Florex and by recrystallization from ether-hexane toafford the title compound (.71 g.), m.p. 159°-163°; ultravioletabsorption peak at 240 mμ (ε15,900); infrared absorption peaks at 6.00μ.

C₂₃ H₃₂ O₂ Calculated: C, 81.1%; H, 9.5%. Found: C, 80.8%; H, 9.3%.

The compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 187 13β-n-Butyl-17α-ethyl-17β-hydroxy-gon-4-en-3-one

Keep a solution of13β-n-butyl-3-methoxy-17α-ethyl-gona-2,5(10)-dien-17β-ol (1.05 g.) in amixture of tetrahydrofuran (15 cc.), methanol (54 cc.), 12N hydrochloricacid (3.6 cc.) and water (2.4 cc.) for 2 hours at room temperature andthen pour into brine (350 cc.). Work up with ether and dissolve theproduct, a gum (1.0 g.), in a mixture of light petroleum and benzene (25cc.) and chromatograph on silica gel. Elute with benzene containing asmall proportion of ether to give a crystalline by-product (0.1 g.);subsequently elute with a mixture of ether, benzene and chloroform (inthe proportions 5:4:1 by volume) to yield a crystalline product.Recrystallize the latter from hexane, and subsequently from hexanecontaining a little ethyl acetate to obtain the title compound (0.23g.), m.p. 78°-80°; ultraviolet absorption peak at 240 mμ (ε14,700);infrared absorption peaks at 2.88, 6.00, 6.18 μ.

This compound has anabolic, androgenic and estrogen antagonisticactivity and is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 188 13β,17α-Diethyl-17β-hydroxy-gon-4-en-3-one

Treat 13β,17α-diethyl-17β-hydroxy-gon-5(10)-en-3-one (12.2 g.) with asolution of methanol (442 cc.), water (22 cc.) and concentratedhydrochloric acid (30 cc.) and allow the mixture to stand at roomtemperature for 2 hours. Precipitate the product by the addition ofwater, extract the reaction mixture with ether and wash the etherealsolution with 10% aqueous sodium carbonate, brine and dry (MgSO₄).Evaporate the solvent and recrystallize the residue from acetonitrile togive the title compound 7.9 g. (64.8%), m.p. 144°-5°; infraredabsorption 2.92, 6.0, 6.2 μ; ultraviolet absorption λmax. 240 mμ(ε15,680).

C₂₁ H₃₂ O₃ Calculated: C, 79.86%; H, 10.04%. Found: C, 79.70%; H,10.19%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 189 13β-Ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one

Stir 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-5(10)-en-3-one (0.1 g.) witha mixture of methanol (36 cc.), water (1.6 cc.) and concentratedhydrochloric acid (2.4 cc.) for 1 hour. Add water and extract themixture with ether. Wash, dry and evaporate the ethereal solution andrecrystallize the residue from ether-hexane to obtain the titlecompound, m.p. 203°-6° undepressed on admixture with authentic material.Infrared spectrum 3.05, 3.5, 6.05, 9.4 μ.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 190 13β,17α-Diethyl-17β-hydroxy-gon-4-en-3-one

Add 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (1 g.) in benzene(15 cc.) and ethanol (5 cc.) to a pre-reduced suspension of 2% palladiumon calcium carbonate (0.3 g.) in benzene (10 cc.) and shake the mixturein an atmosphere of hydrogen until 163 cc. (2.1 moles) of hydrogen hasbeen absorbed. Filter off the catalyst, evaporate the solvent and shakethe product (0.55 g.) in methanol (10 cc.) with a solution of sodiummetabisulphite (1.7 g.) in water (8 cc.) for 5 minutes. Add water,extract the mixture with ether; wash, dry and evaporate the etherealsolution and recrystallize the product from acetone to obtain the titlecompound (0.4 g.), m.p. 144° undepressed on admixture with authenticmaterial; infrared spectrum 2.9, 6.0, 6.18; ultraviolet spectrum max.241 mμ (ε17,250).

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 191 17β-Ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one

Treat 13β-ethyl-3-ethoxy-17α-ethynyl-gona-3,5-dien-17β-ol (0.1 g.) witha mixture of methanol (10 cc.) and 50% hydrochloric acid (1 cc.) andallow the mixture to stand at room temperature for 1 hour. Add water,filter off the precipitated product and recrystallize from ethylacetate-hexane to yield the title compound, identical with authenticmaterial by mixed melting point determination and comparison of infraredspectra.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 192 13β, 17α-Diethyl-17β-hydroxy-gonan-3-one

Dissolve 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-4-en-3-one (1.5 g.) inethanol (50 cc.) and shake with 10% palladium on charcoal (0.9 g.) in anatmosphere of hydrogen until uptake of hydrogen ceases. Filter off thecatalyst, evaporate the solvent and recrystallize the residue frometherhexane to afford title compound, m.p. 192°-196°.

C₂₁ H₃₄ O₂ Calculated: C, 79.19%; H, 10.76%. Found: C, 79.4%; H, 10.43%.

This compound has estrogen antagonistic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 19313β-Ethyl-3-methoxy-17α-ethynyl-17β-acetoxy-gona-1,3,5(10)-triene

Shake 13β-ethyl-3-methoxy-17α-ethynyl-gona-1,3,5(10)-trien-17β-ol (1.1g.) with toluene-p-sulphonic acid (0.3 g.) and acetic anhydride (10 cc.)until the solution is homogeneous and then allow to stand at roomtemperature for 12 hours. Decompose the reaction mixture by stirringwith water containing a little pyridine and extract with ether. Wash theethereal solution with water, 2N aqueous sodium hydroxide, water, dilutehydrochloric acid, brine and dry (MgSO₄). Evaporate the solvent anddissolve the crystalline residue in benzene and filter through a shortcolumn of alumina. Recrystallize the product from methanol-ethyl acetateto obtain the title compound 0.98 g., m.p. 178°-182°; infraredabsorption peaks at 3.02, 5.75 μ.

This compound has estrogenic activity and is useful as an intermediatefor preparing the hormonal compounds of this invention.

EXAMPLE 19413β-Ethyl-3-methoxy-17α-dibromoacetyl-17β-acetoxy-gona-1,3,5(10)-triene

Dissolve13β-ethyl-3-methoxy-17α-ethynyl-17β-acetoxy-gona-1,3,5(10)-triene (0.6g.) in tertiary butanol (25 cc.) and water (0.4 cc.) and addN-bromoacetamide (0.55 g.). Allow the mixture to stand for 15 hours,then add water (10 cc.), cool to 0° and allow to stand for 3 hours.Filter the precipitated product, wash with aqueous methanol and dry toobtain the title product (0.72 g.), m.p. 85°-92° .

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 19513β-Ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)-triene

Heat13β-ethyl-3-methoxy-17α-dibromoacetyl-17β-acetoxy-gona-1,3,5(10)-triene(0.7 g.) in acetic acid (27 cc.) and water (2.7 cc.) with sodium acetate(0.7 g.) and zinc dust (0.99 g.) at 100° for 15 minutes with stirring.Filter the mixture, add water to the filtrate and filter theprecipitated product. Dry the residue and recrystallize from ethylacetate-methanol to obtain the title product (0.25 g.), m.p. 144°-8°;infrared absorption peaks at 5.8, 5.9 μ.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 196 13β-Ethyl-17β-acetylgon-4-en-3-one

Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)triene(0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.)in liquid ammonia (100 cc.). After 30 minutes add methanol (8 cc.)followed by lithium (0.5 g.) in small pieces. Add water, extract withether and work up to a gum (0.218 g.). Reflux this product with 4Nhydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Addwater, extract with ether, work up and dissolve the resulting gum inacetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) andadd 8N-chromic acid dropwise with swirling until the solution assumes apermanent yellowish-orange color. Add excess isopropanol and evaporatethe solution almost to dryness. Add water, extract with ether, wash, dryand evaporate the organic solution, filter the product through aluminawith benzene-ether and recrystallize the product from ethyl acetate toobtain the title product (0.072 g.), m.p. 138°-142°; infrared absorptionpeaks at 5.9, 6 μ.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 197 13β-Ethyl-gon-4-en-17β-ol

Add 13β-ethyl-3,3-ethylenedithio gon-4-en-17β-ol in ether (5 cc.) andtetrahydrofuran (2 cc. to a stirred solution of liquid ammonia (50 cc.)and add sodium (0.5 g.) in pieces and then add ethanol dropwise todischarge the blue color. Add ammonium chloride and water, extract withether and wash, dry and evaporate the organic solution. Recrystallizethe residue from light petroleum, b.p. 60°-80°, to obtain13β-ethyl-gon-4-en-17β-ol, m.p. 118°-120°.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 198 13β-Ethyl-gon-4-en-17-one

Dissolve 13β-ethyl-gon-4-en-17β-ol (0.29 g.) in acetone (40 cc.) and8N-chromic acid dropwise with stirring until the solution becomespermanently orange and then add isopropanol (3 cc.) and evaporate thesolution to small bulk (ca. 5 cc.). Add water and extract the mixturewith ether. Wash, dry and evaporate the ethereal solution to obtain13β-ethyl-gon-4-en-17-one (0.24 g.), m.p. 101°-102° C. Purify byrecrystallization from methanol to obtain the pure product, m.p.102.5°-103.5° C.

C₁₉ H₂₈ O Calculated: 83.8%; H, 10.4%. Found: 83.55%; H, 10.7%.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 199 13β-Ethyl-17α-allyl-gon-4-en-17β-ol

Reflux magnesium (0.36 g.) and allyl bromide (0.15 cc.) in dry ether (10cc.) for 15 minutes and then add 13β-ethyl-gon-4-en-17-one (0.9 g.) inether (40 cc.) containing allyl bromide (2.9 cc.). Reflux the mixturefor 3 hours and treat the cooled solution with aqueous ammoniumchloride. Extract the product with ether and wash the ethereal solutionwith water, brine and dry (MgSO₄). Evaporate the solvent andrecrystallize the residue from methanol to obtain13β-ethyl-17α-allyl-gon-4-en-17β-ol (0.97 g.), m.p. 88.5°-91° C.Recrystallize further from ether-hexane to obtain the pure product, m.p.92°-94° C.

C₂₂ H₃₄ O Calculated: C, 84.0%; H, 10.9%. Found: C, 84.4%; H, 10.9%.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 200 13β-n-Propyl-3,3-ethylenedithio-gon-4-en-17β-ol

Treat 13β-n-propyl-17β-hydroxy-gon-4-en-3-one (6 g.) in acetic acid (15cc.) with ethane dithiol (1.75 cc.) followed by boron trifluorideetherate (1.75 cc.). Allow the mixture to stand at room temperature for15 minutes then pour into water and filter. Recrystallize the residuefrom methanol to obtain the title product, (6.05 g.), m.p. 165°-166.5°C. Recrystallize further to obtain the pure compound, m.p. 167°-168.5°C.

C₂₂ H₃₄ OS₂ Calculated: C, 69.8%; H, 9.05%; S, 26.9%. Found: C, 69.6%;H, 8.9%; S, 16.5%.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 201 13β-n-Propyl-gon-4-en-17β-ol

Add 13β-n-propyl-3,3-ethylenedithio-gon-4-en-17β-ol (5.8 g.) intetrahydrofuran (40 cc.) and ether (20 cc.) with stirring to a solutionof sodium (3 g.) in liquid ammonia (250 cc.). Add more sodium (3 g.) inpieces over 30 minutes followed by the dropwise addition of ethanol todischarge the blue color. Add water, extract with ether and wash, dryand evaporate the organic extracts. Recrystallize the product fromether-hexane to obtain the title product (4.5 g.), m.p. 115°-119° C.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 202 13β-n-Propyl-gon-4-en-17-one

Add 8N chromic acid dropwise with stirring to a solution of13β-n-propyl-gon-4-en-17β-ol in acetone (100 cc.) until the solutionbecomes permanently orange. Add isopropanol (10 cc.) and potassiumcarbonate (5 g.), filter and evaporate the filtrate to dryness. Filterthe residue in benzene-ether (1:1) through neutral alumina (20 g.),evaporate and recrystallize the product from methanol to obtain13β-n-propyl-gon-4-en-17-one. Recrystallize from ether-hexane to obtainthe pure product, m.p. 89°-90° C.

C₂₀ H₃₀ O Calculated: C, 83.3; H, 10.6%. Found: C, 83.9; H, 10.5%.

This compound is useful as an intermediate for preparing the hormonalcompounds of this invention.

EXAMPLE 203 13β-n-Propyl-17α-ethynyl-gon-4-en-17β-ol

Add 13β-n-propyl-gon-4-en-17-one (1.5 g.) in dimethylacetamide (50 cc.)to a stirred suspension of lithium acetylide (40 cc. of a 15% solutionin dioxan-triethylamine) and pass a slow stream of acetylene through thestirred solution for 40 hours. Pour the mixture into iced water andextract with ether. Wash and dry the ethereal solution and evaporate todryness. Recrystallize the product twice from methanol and once fromhexane to obtain the title product, m.p. 118°-119° C.

C₂₂ H₃₂ O Calculated: C, 84.55%; H, 10.3%. Found: C, 84.8%; H, 10.4%.

This compound has progestational activity and is useful for preparingthe hormonal compounds of this invention.

EXAMPLE 204 13β-n-Propyl-17α-allyl-gon-4-en-17β-ol

Reflux magnesium (0.36 g.) and allyl bromide (1.5 cc.) in ether (15 cc.)for 15 minutes and then add a solution of 13β-n-propyl-gon-4-en-17-onein ether (10 cc.) and allyl bromide (2.9 cc.). Reflux for 3 hours andtreat the cooled solution with aqueous ammonium chloride. Extract themixture with ether and wash, dry, and evaporate the ethereal solution.Recrystallize the residue from methanol and then from hexane to obtain13β-n-propyl-17α-allyl-gon-4-en-17β-ol, m.p. 90°-92° C.

C₂₃ H₃₆ O Calculated: C, 84.1%; H, 11.1%. Found: C, 84.15%; H, 11.1%.

This compound has progestational activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 205 13β,17α-Diethyl-gon-4-en-3,17β-diol

Add 13β,17α-diethyl-17β-hydroxy-gon-4-en-3-one (10 g.) intetrahydrofuran (100 cc.) and ether (100 cc.) to a stirred suspension oflithium aluminum hydride (5 g.) in ether (1000 cc.). Reflux the mixturefor 2 hours, cool and decompose excess reagent by cautiously addingwater. Separate the organic phase, wash, dry and evaporate to obtain thetitle product (10 g.), m.p. 110°-122° C.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 206 13β,17α-Diethyl-3-acetoxy-gon-4-en-17β-ol

Allow 13β,17α-diethyl-gon-4-en-3,17β-diol (3 g.) in pyridine (30 cc.)and acetic anhydride (3 cc.) to stand for 12 hours at 0° C. Evaporatethe solvents under reduced pressure at less than 50° C. and crystallizethe residue from ether-hexane to obtain the title product (2.43 g.),m.p. 85°-100° C.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 207 13β,17α-Diethyl-gon-4-en-17β-ol

Add 13β,17α-diethyl-3-acetoxy-gon-4-en-17β-ol (1.35 g.) in ether (50cc.) to a stirred solution of lithium (0.5 g.) in redistilled ethylamine(100 cc.). Stir the mixture for 15 minutes and decompose excess reagentwith sodium nitrite. Allow the ethylamine to evaporate and add sodiumsodium sulphate (10 g.) and ether (200 cc.). Evaporate the filteredethereal solution and recrystallize the residue from ether-hexane togive the title product, m.p. 96°-112° C. Chromatograph on neutralalumina, eluting with benzene containing 5% ether and recrystallize fromether to obtain the pure compound, m.p. 117.5°-118.5° C.

C₂₁ H₃₄ O Calculated: C, 83.4%; H, 11.3%. Found: C, 83.5%; H, 11.3%.

This compound has anabolic and androgenic activity and is useful as anintermediate for preparing the hormonal compounds of this invention.

EXAMPLE 208 dl-13-Ethyl-17-ethynylgon-4-en-17β-ol

Stir 13-ethylgon-4-en-17-one (2.1 g) with lithium acetylide (4.5 g) indimethylacetamide (60 ml) for 60 hours. Recrystallize twice frommethanol to obtain the title compound (1.13 g), m.p. 106°-108°.Chromatograph on neutral alumina (35 g) and recrystallize from methanoland then from ether-hexane to obtain an analytical sample with m.p.109°-110°; infrared absorption peaks at 2.8 μ, 3.6 μ.

C₂₁ H₃₀ O Calculated: C, 84.51%; H, 10.13%. Found: C, 84.43%; H, 9.86%.

This compound has progestational activity.

EXAMPLE 209 dl-17α-Allyl-17-hydroxy-13-propylgon-4-en-3-one

Treat dl-3-methoxy-13-propylgona-2,5(10)-dien-17-one (2.0 g) with allylmagnesium bromide to obtain a glass that is a mixture ofdl-17α-allyl-3-methoxy-13-propylgona-2,5(10)-dien-17-ol (minorcomponent) and the Δ⁵(10) -3-keto and Δ⁴ -3-keto compounds (majorcomponent). Hydrolyze the mixture (in two portions) with hydrochloricacid-isopropanol-water, then chromatograph and crystallize the resultantcrude product to obtain the title compound (22% from the startingmaterial), m.p. 135°-137°; ultraviolet absorption peak at 241.5 mμ(ε17,470), infrared maxima at 2.95 μ (OH), 6.03 μ, 6.18 μ(α,β-unsaturated carbonyl), 10.93 μ (R--CH=CH₂).

C₂₃ H₃₄ O₂ Calculated: C, 80.65%; H, 10.01%. Found: C, 80.39%; H, 9.77%.

This compound has progestational activity.

EXAMPLE 210 dl-3-(17β-Hydroxy-3-oxo-13-propylgon-4-en-17α-yl)propionicacid, γ-lactone

Add dl-17α-ethynyl- 3-methoxy-13-propylgona-1,3,5(10)-trien-17β-ol (8.7g) in tetrahydrofuran (200 ml) with stirring to 3 moles of etherealmethyl magnesium bromide (100 ml). Stir the mixture, distil until theboiling point of the distillate reaches 63°. Keep the mixture at refluxwith stirring for 21 hours and add the cooled mixture with swirling tosolid carbon dioxide (ca. 1 kg). After 1.5 hours acidify the mixturewith sulfonic acid and extract with ether. Extract the ether solutionwith aqueous sodium hydrogen carbonate and acidify the extracts toobtaindl-3-(17β-hydroxy-3-methoxy-13-propylgona-1,3,5(10)-trien-17α-yl)prop-2-ynoicacid. Recycle the neutral material to obtain further acid. Hydrogenatethis acid (4.3 g) in ethanol (100 cc) containing 5% palladized charcoal(3 g). Add the product (3.05 g), m.p. 183°-191°, to sodium hydroxide(0.32 g) in methanol and evaporate the resulting solution to dryness.Reduce the residue with lithium (5 g) in liquid ammonia (300cc)-tetrahydrofuran (50 cc)-t-butanol (50 cc). Keep the product at roomtemperature for two hours in methanol (50 ml)-water (10 ml)-concentratedhydrochloric acid (5 ml). Purify the product by sublimation,chromatography and recrystallization from acetone to obtain the titlecompound, m.p. 197°-199.5°, λmax. 240.5 mμ (ε16,800); infraredabsorption peaks at 5.67, 6.01, and 6.21 μ.

C₂₃ H₃₂ O₃ Calculated: C, 77.5%; H, 9.05%. Found: C, 76.6%; H, 8.95%.

This compound has aldosterone blocking activity.

EXAMPLE 211 dl-17β-Hydroxyestr-4-en-3-one 3-phenylpropionate(dl-19-Nortestosterone 3-phenylpropionate)

Dissolve dl-17β-hydroxyestr-4-en-3-one (0.3 g) in pyridine (1 ml) cooledto -15°. Allow the mixture to stand at -10° for 15 hours. Pour intowater and extract with benzene. Wash the organic extracts successivelywith 10% aqueous sodium hydroxide, 10% hydrochloric acid, water, andbrine. Dry over sodium sulfate and evaporate. Filter the residue througha short column of alumina with benzene and recrystallize from ethylacetate-light petroleum ether to obtain the title compound, m.p.120°-122°; ultraviolet absorption peak at 241 mμ (ε16,900), infraredmaxima at 5.8 μ, 6.05 μ.

This compound has anabolic activity.

EXAMPLE 212 dl-17α-Chloroethynyl-17-hydroxy-13-propylgon-4-en-3-one

Treat dl-3-methoxy-13-propylgona-2,5(10)-dien-17-one (8.0 g) in ether(250 cc) with chloroethynyl lithium prepared from methyl lithium (5.53%,.35 M) (100 cc) and dichloroethylene (16.9 g, .175 M) in ether. Stir for20 hours under nitrogen. Wash, dry and evaporate the ether layer.Triturate the residue with hot methanol (225 cc) to obtaindl-3-methoxy-17α-chloroethynyl-17-hydroxy-13-propylgona-2,5(10)-diene(2.5 cc), m.p. 110°-116°, λmax. CHCl₃ 4.55, 5.94, 6.04 μ.

Hydrolyze crudedl-3-methoxy-17α-chloroethynyl-17-hydroxy-13-propyl-gona-2,5(10)-dienewith water (4 cc), methanol (90.0 cc), HCl (6.0 cc) and isopropanol (10cc) under nitrogen. Pour into brine and extract with ether.Chromatograph the crude product on Florex (200 g). Elute with 5%ether-95% benzene and recrystallize from ethyl acetatehexane to obtainthe title compound (1.10 g), m.p. 179°-181° C; λmax. KBr 2.90, 4.53,6.03 μ; λmax. EtOH 240 mμ (ε16,900).

C₂₂ H₃₂ ClO₂ Calculated: C, 73.21%; H, 8.10%; Cl, 9.82%. Found: C,73.51%; H, 8.19%; Cl, 9.9%.

This compound has progestational activity.

EXAMPLE 213 dl-17α-Chloroethynyl-13-ethyl-17-hydroxygon-4-en-3-one

Carry out an Oppenauer oxidation ondl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol (70 g) in the usual mannerto obtain dl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one (58 g, 83%yield). Combine this material with a further 5.5 g. ofdl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one. Prepare a solution ofapproximately 0.5 mole of lithium chloroacetylide in ether in thefollowing manner. Transfer, under nitrogen, a solution of methyl lithium(23.6 g) in ether (406 g) to a 2-liter, 3-necked flask equipped withdry-ice condenser. Cool in ice to 0°. Add trans-dichloroethylene (60 g)dropwise with stirring. Allow the resultant mixture to come to roomtemperature before adding the steroid.

Add the enol ether as a slurry in tetrahydrofuran (500 ml) to thesolution of lithium chloroacetylide in ether. Stir the steadilydarkening solution for 2 hours, then work up by addition of ice water(500 ml), followed by extraction in the usual manner. Evaporate thesolvent and triturate the residue with hot methanol to obtain17α-chloroethynyl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol (73 g).

Dissolve 17α-chloroethynyl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol(65 g) in the minimum volume of tetrahydrofuran and add to a stirredmixture of methanol (720 ml), concentrated hydrochloric acid (48 ml),and water (32 ml). Stir until all the precipitated material hasdissolved. Stir the mixture for a further 30 minutes, when the titlecompound will begin to crystallize out. Then slowly add water (2 liters)to precipitate the rest of the product, filter off, wash thoroughly withdistilled water, and partially dry in a desiccator. Take up the crudematerial in hot ethyl acetate and charcoal with Norit (30 g). Thistreatment will remove almost all the color. Evaporate the solvent andcrystallize the material from methanol (400 ml) and water (130 ml) toobtain the title compound (54 g); infrared absorption peak at 5.75 μ.Crystallize further from methanol (300 ml) and water (100 ml) to obtainan analytical sample (43 g) with m.p. 186°-189°; ultraviolet absorptionpeak at 240 mμ (ε16,100); infrared maxima at 3.05 μ, 4.6 μ, 6.05 μ.

C₁₉ H₂₇ ClO₂ Calculated: C, 72.71%; H, 7.85%; Cl, 10.22%. Found: C,72.75%; H, 7.77%; Cl, 10.20%.

This compound has progestational activity.

EXAMPLE 214 dl-6-Dibromomethylene-13-ethylgon-4-ene-3,17-dione

and

dl-13-Ethyl-6-methylgon-4-ene-3,17-dione

React dl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol (50.2 g) accordingto the Oppenauer oxidation procedure to obtaindl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one, m.p. 126°-143°; noaromatic system shown by ultraviolet absorption, infrared absorptionpeaks (potassium bromide) at 5.78 μ, 6.09 μ, 6.18 μ.

Treat dl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one with hydrochloricacid in aqueous methanol to obtain dl-13-ethylgon-4-ene-3,17-dione(25.6, 54% from dl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol), m.p.156°-157.5°; ultraviolet absorption peak in 95% ethanol at 240.5 mμ(15,900), infrared maxima (potassium bromide) at 5.77 μ, 5.98 μ .Recrystallize dl-13-ethylgon-4-ene-3,17-dione (1.0 g) three times fromethyl acetate to obtain 484 mg., 157°-159.5°; ultraviolet absorptionpeak (95% ethanol) at 240 mμ (ε17,200), infrared maxima (potassiumbromide) at 5.77 μ, 5.98 μ.

React dl-13-ethylgon-4-ene-3,17-dione (5.0 g) in dioxane with ethylorthoformate and toluene-p-sulfonic acid at room temperature for 3 hoursto obtain 4.12 g. (75%) of dl-3-ethoxy-13-ethylgona-3,5-dien-17-one;ultraviolet absorption peak (95% ethanol) at 242 mμ (ε12,150), infraredabsorption peak (potassium bromide) at 5.78 μ.

Stir at room temperature dl-3-ethoxy-13-ethylgona-3,5-diene-17-one (1.88g) with carbon tetrabromide (4.0 g) in collidine (17.5 ml) and pyridine(2.5 ml) for 40 hours. Filter off the solid and wash with a littlepyridine. Acidify the filtrate with cold dilute hydrochloric acid andextract the product into ether. Wash, dry, and concentrate the etherealsolution to approximately 10 ml. Add pyridine (50 ml) and heat at 100°for 30 minutes under nitrogen. Cool and acidify the solution and extractwith ether. Evaporate the washed, dried ethereal extracts andcrystallize the residue from ether to obtaindl-6-dibromomethylene-13-ethylgon-4-ene-3,17-dione (1.44 g). Purify bychromatography on deactivated alumina (40 g), eluting withbenzene-petroleum ether (1:1) to obtain 0.862 g. (29%), m.p. 149°-153°.Recrystallize from tetrahydrofuran-ether to obtain the analyticalsample, m.p. 163.5°-165.5°; ultraviolet absorption peaks at 249 mμ(ε10,540), 283-288 mμ (ε6,650); infrared maxima (chloroform) at 5.78 μ,5.99 μ, 6.21 μ, 6.38 μ.

C₂₀ H₂₄ Br₂ O₂ Calculated: C, 52.65%; H, 5.30%; Br, 35.0%. Found: C,52.85%; H, 5.08%; Br, 32.8%.

Hydrogenate dl-6-dibromomethylene-13-ethylgon-4-ene-3,17-dione for 2hours in the presence of dioxane and triethylamine, using 2%palladium-strontium carbonate as a catalyst. Filter off the catalyst,acidify the filtrate with 1N hydrochloric acid, and allow to stand forone hour. Extract with ether and triturate with methanol to obtaincrystals of starting material (100 mg). Concentrate the liquors toobtain 86 mg. of crystals; ultraviolet absorption peak (95% ethanol)241.5 mμ (ε13,950). Chromatograph on a column of deactivated neutralalumina, eluting with benzene-petroleum ether (1:1) to obtaindl-13-ethyl-6-methylgon-4-ene-3,17-dione (26 mg), m.p. 141°-149°;ultraviolet absorption peak (95% ethanol) at 242.5 mμ (ε15,450),infrared maxima (potassium bromide) at 5.78 μ, 6.00 μ.

EXAMPLE 215 dl-13-Ethyl-17β-(2-hydroxyethoxy)gon-4-en-3-one, benzoate

Prepare a solution of ether (100 ml), aluminum chloride (13.3 g) andlithium aluminum hydride (15 ml. of a 1 M solution). Stir for 20minutes. Add to a cool solution ofdl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17-one, cyclic ethylene ketal(17.1 g) in ether (1,000 ml). Stir the reaction mixture and cool in anice-water bath for 4 hours. Dilute with 2 N sulfuric acid until a clearsolution results. Separate the ether layer, wash with saturated sodiumbicarbonate solution, and evaporate. Treat the residue with ethanol (200ml), concentrated hydrochloric acid (5 ml) and water (10 ml) on a steambath for 30 minutes. Evaporate, then recrystallize from ethanol toobtain dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene(8.1 g), m.p. 131°-132°; ultraviolet absorption peak at 278 mμ (ε2,130),infrared maximum at 2.93 μ.

C₂₂ H₃₂ O₃ Calculated: C, 76.70%; H, 9.36%. Found: C, 76.81%; H, 9.35%.

Dissolvedl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene (4.0 g)in 1-methoxy-2-propanol (60 ml), tetrahydrofuran (120 ml) and liquidammonia (300 ml). Gradually add lithium (4.0 g) with stirring over aperiod of 1 hour. Add ammonium chloride (8.0 g) and water. Filter, washand dry the resulting precipitate. Dissolve the product intetrahydrofuran (300 ml) and liquid ammonia (300 ml) and treat withlithium (4.0 g). Stir for 1 hour. Add absolute ethanol, then water.Filter the resulting precipitate and wash it with water to obtaindl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-2,5(10)-diene (3.4 g);essentially no ultraviolet absorption at the 280 mμ region, infraredabsorption maxima at 2.91 μ, 5.89 μ, 6.0 μ.

Suspend dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-2,5(10)-diene(1.7 g) in methanol (100 ml), concentrated hydrochloric acid (8 ml) andwater (5 ml) and stir the suspension for 2 hours under nitrogen. Dilutethe clear solution with water and separate the product with ether. Washthe organic layer with a saturated sodium bicarbonate solution and dryover magnesium sulfate. Evaporate the ether to obtain a gum,dl-13-ethyl-17β-(2-hydroxyethoxy)gon-4-en-3-one (1.39 g); ultravioletabsorption peak at 240 mμ (ε13,200), infrared maxima at 2.95 μ, 6.0 μ.

Treat a solution of dl-13-ethyl-17β-(2-hydroxyethoxy)gon-4-en-3-one (1.3g) in pyridine (6 ml) with benzoyl chloride (1.3 moles) at -10°. Keepthe reaction mixture at -10° for 16 hours. Pour over ice and separatethe product with ether. Wash the organic layer consecutively with 2 Nhydrochloric acid, 2 N sodium hydroxide, water, and brine, then dry overmagnesium sulfate. Evaporate the solvent, chromatograph the gum onneutral alumina, and elute with benzene-ethyl acetate to obtain thetitle compound (800 mg); ultraviolet absorption peak at 233 mμ(ε25,500), infrared maxima at 5.8 μ, 5.98 μ.

C₂₈ H₃₆ O₄ Calculated: C, 77.03%; H, 8.31%. Found: C, 77.44%; H, 8.59%.

This compound has anabolic activity.

EXAMPLE 216 dl-17β-Hydroxyestr-4-en-3-one

Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g) in methanol (18ml) containing concentrated hydrochloric acid (1.2 ml) and water (0.8ml) and allow the mixture to stand at room temperature for 15 hours. Addwater and extract the mixture with ether. Wash, dry and evaporate theethanol solution and dissolve the residue in a little benzene. Filterthrough a column of alumina (25 g) with benzene-ether (7.3). Evaporatethe eluates and recrystallize the residue from etherhexane to obtain thetitle compound (372 mg), m.p. 123°-124.5° or in an alternate form, m.p.131°-132°; ultraviolet absorption maximum at 241 mμ (ε16,600); infraredabsorption peaks at 6μ, 7.9 μ, 9.4 μ.

C₁₈ H₂₆ O₂ Calculated: C, 78.8%; H, 9.55%. Found: C, 79.08%; H, 9.54%.

This compound has anabolic activity.

EXAMPLE 217 dl-13-Ethylgon-4-ene-3,17-dione, 17-cyclic ethylene ketal

Add dl-13-ethyl-17,17-ethylenedioxy-3-methoxygona-1,3,5(10)-triene (0.35g) in tetrahydrofuran (20 ml) to a stirred solution of lithium (0.5 g)in liquid ammonia (100 ml). Stir the mixture for 5 minutes and then addethanol (10 ml) dropwise. When the blue color is discharged, addsaturated aqueous ammonium chloride and collect the product in ether.Evaporate the solvent and crystallize the residue from ethanol. Dissolvethe product in ethanol (30 ml) and tetrahydrofuran (5 ml) and stir withoxalic acid dihydrate (0.45 g) in water (6 ml) for 1 hour. Add excess20% aqueous potassium hydroxide, water and collect the product in ether.Wash, dry and evaporate the ethereal solution and filter the residuethrough a Florex column with benzene-ether (9:1). Recrystallize theproduct from heptane to obtain the title compound (105 mg), m.p.129°-131°; ultraviolet absorption peak at 240 mμ (ε16,000), infraredmaxima at 6.0 μ, 6.2 μ, 8.6 μ .

C₂₁ H₃₀ O₃ Calculated: C, 76.32%; H, 9.15% Found: C, 76.47%; H, 9.04%

This compound has estrogen antagonistic activity.

EXAMPLE 218 dl-13-Ethyl-17a β-hydroxy-17a-methyl-D-homogon-4-en-3-one

Reflux dl-13-ethyl-3-methoxy-D-homogona-1,3,5(10),8-tetraen-17a-one(13.3 g) for 8 hours with 3 M methyl magnesium bromide (200 ml) inbenzene and recrystallize from methanol to obtain 9.2 g. of the Grignardproduct,dl-13-ethyl-17a-methyl-17a-hydroxy-D-homogona-1,3,5(10),8-tetraene;ultraviolet absorption peak at 276 mμ (ε15,500), infrared analysisindicating no remaining carbonyl band. Reduce the 8,9-double bond withlithium (1.5 g), liquid ammonia (450 ml), tetrahydrofuran (170 ml) andaniline (30 ml) to obtain the crude D-homo estradiol methyl ether (8.0g), m.p. 153°-163°; ultraviolet absorption peak at 280 mμ (ε1,314).Reduce further with lithium and ethanol in liquid ammonia to obtaindl-13-ethyl-3-methoxy-17a-methyl-17a-hydroxy-D-homogona-2,5(10)-diene(7.2 g), m.p. 175°-180°. Hydrolyzedl-13-ethyl-3-methoxy-17a-methyl-17a-hydroxy-D-homogona-2,5(10)-dienewith hydrochloric acid-methanol-water. Carefully chromatograph on 300 g.Grade III neutral alumina and recrystallize from ethyl acetate-hexane toobtain the title compound (3.35 g), m.p. 129.5°-130.5°; ultravioletabsorption peak at 242 mμ (ε17,100).

C₂₁ H₃₂ O₂ Calculated: C, 79.70%; H, 10.19% Found: C, 79.99%; H, 10.08%

This compound has progestational and anabolic activities.

EXAMPLE 219 dl-17a β-Hydroxy-13-propyl-D-homogon-4en-3-one

Dissolve 2-propylcyclohexane-1,3-dione (36.3 g) in benzene (400 cc)containing pyridine (21.2 cc). Add 6-m-methoxyphenylhex-1-en-3-one (43.2g) and reflux the solution over night. Cool the reaction mixture, washwith water, aqueous sodium carbonate, and 10% aqueous sulfuric acid, dryand remove the solvents under reduced pressure to obtain2-(6-m-methoxyphenyl-3-oxohexyl)-2-propylcyclohexane-1,3-dione.

Heat 2-(6-m-methoxyphenyl-3-oxohexyl)-2-propylcyclohexane-1,3-dione(43.0 g) in benzene (400 cc) with polyphosphoric acid (250 g) for 3hours at 60° with vigorous stirring. Add ice water (400 cc) and separatethe benzene layer. Extract the water with ether, combine the organiclayers; wash, dry and evaporate. Recrystallize this residue from ethanol(250 cc) to obtaindl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8,14-pentaen-17a-one (27.6g), m.p. 86°-89°C, λmax. KBr 5.87 μ, 6.25 μ; λmax. EtOH 312 mμ(ε24,300).

C₂₂ H₂₆ O₂ Calculated: C, 81.95%; H, 8.13%. Found: C, 82.11%; H, 8.18%.

Hydrogenatedl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8,14-pentaen-17a-one (27.6g) dissolved in tetrahydrofuran (250 cc) over 2% Pd/CaCO₃ (7.0 g).Uptake of one mole requires 15 minutes. Filter, remove solvent and boilwith 95% ethanol (250 cc). Filter to obtaindl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8-tetraen-17a-one (25.5 g),m.p. 146°-148°C, λmax. EtOH 277 mμ (ε16,130).

C₂₂ H₂₈ O₂ Calculated: C, 81.42%; H, 8.69%. Found: C, 81.30%; H, 8.62%.

Reflux dl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8-tetraen-17a-one (20g) in ethanol (250 cc) with sodium borohydride (7.0 g) for one hour.Make acid with 50% aqueous acetic acid, add water (500 cc), filter, washand recrystallize from ethanol (250 cc) to obtaindl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8-tetraen-17a β-ol (16.0 g),m.p. 122°-124°, λmax. KBr 3.02 μ, 6.25 μ; λmax. EtOH 275 mμ (ε16,325).

C₂₂ H₃₀ O₂ Calculated: C, 80.92%; H, 9.27%. Found: C, 80.74%; H, 9.81%.

Add dl-3-methoxy-13-propyl-D-homogona-1,3,5(10),8-tetraen-17a β-ol (16.0g) dissolved in tetrahydrofuran (100 cc) and aniline (100 cc) to liquidammonia (900 cc) containing tetrahydrofuran (250 cc). Add lithium metal(1.0 g), stir for one hour and discharge the blue color by addition ofwater. Extract the product with ether, remove aniline by shaking withdilute hydrochloric acid, and wash, dry and evaporate the solvent.Recrystallize twice from methanol to obtaindl-3-methoxy-13-propyl-D-homogona-1,3,5(10)-trien-17a β-ol (13.0 g),m.p. 123°-125°, λmax. EtOH 280 mμ (ε1,900).

C₂₂ H₃₂ O₂ Calculated: C, 80.43%; H, 9.82%. Found: C, 80.33%; H, 9.90%.

Treat dl-3-methoxy-13-propyl-D-homogona-1,3,5(10)-trien-17a β-ol (13.0g) dissolved in tetrahydrofuran (240 cc) and liquid ammonia (500 cc)with lithium metal (3.5 g). Stir 1.5 hours, discharge the blue color bydropwise addition of absolute ethanol, add water and filter the crudeproduct. Triturate with methanol (110 cc) to obtaindl-3-methoxy-13-propyl-D-homogona-2,5(10)-dien-17aβ-ol (11.4 g), m.p.150°-157°, λmax. KBr 3.09 μ, 5.90 μ, 6.0 μ.

Hydrolyze dl-3-methoxy-13-propyl-D-homogona-2,5(10)-dien-17a β-ol (1.4g) with methanol (80 cc) concentrated hydrochloric acid (6.0 cc) andwater (4.0 cc) and isolate the product. Recrystallize from ethyl acetateto obtain the title compound (0.80 g), m.p. 150°-152°, λmax. KBr 3.0 μ,6.04 μ; λmax. EtOH 240 mμ (ε16,300).

C₂₁ H₃₂ O₂ Calculated: C, 79.70%; H, 10.19%. Found: C, 79.60%; H,10.10%.

This compound has anabolic activity.

EXAMPLE 220 dl-17β-Hydroxyestr-4-en-3-one, acetate

Add sodium borohydride (8.5 g) to3-methoxyestra-1,3,5(10),8-tetraen-17-one (40 g) in ethanol (500 ml) andreflux the mixture for 90 minutes. Acidify the cooled solution withacetic acid, add water and extract with benzene. Wash, dry and evaporatethe organic extract to obtaindl-3-methoxyestra-1,3,5(10),8-tetraen-17β-ol (37.5 g), m.p. 130°-133°;ultraviolet absorption peak at 280 mμ(ε16,100); infrared maxima at 3.1μ, 3.58 μ, 6.25 μ, 6.4 μ, 6.7 μ.

Add dl-3-methoxyestra-1,3,5(10),8-tetraen-17β-ol (37.5 g) intetrahydrofuran (350 ml) to a stirred solution of liquid ammonia (1liter) and aniline (45 ml). Add lithium (2 g), stir for 30 minutes, andthen add ammonium chloride (20 g) followed by water. Extract withether-benzene (1:1) and wash the organic solution with water, excess 3Nhydrochloric acid, water and dry. Evaporate the solvent andrecrystallize the residue from ethyl acetate-hexane to obtaindl-3-methoxyestra-1,3,5(10)-trien-17β-ol (12 g), m.p. 121°-124°;ultraviolet absorption peak at 278 mμ (ε1,810); infrared maxima at 3.0μ, 6.2 μ, 6.75 μ.

Add dl-3-methoxyestra-1,3,5(10)-trien-17β-ol (1.3 g) in tetrahydrofuran(40 ml) to a stirred solution of lithium (1.3 g) in liquid ammonia (100ml). After 15 minutes add ethanol (20 ml) dropwise and when the bluecolor is discharged add ammonium chloride and water and extract themixture with ether. Wash, dry and evaporate the ethereal solution andrecrystallize the residue from ethanol-hexane to obtaindl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g), m.p. 120°-123°; infraredabsorption maxima at 3.25 μ, 5.8 μ, 6 μ.

Dissolve the foregoing alcohol in ether, add 25% hydrochloric acid. Stirthe mixture at room temperature for 15 minutes and add crushed ice.Evaporate the washed and dried ether layer and recrystallize the residuefrom ether-hexane containing a little ethyl acetate to obtaindl-17β-hydroxyestr-4-en-3-one, m.p. 121°-123°, λmax. 241 mμ (ε17,000).Acetylate the foregoing alcohol with acetic anhydride in pyridine andrecrystallize the product from ether-light petroleum to obtain theester, m.p. 113°-114°, λmax. 242 mμ (ε17,600).

C₂₀ H₂₈ O₃ Calculated: C, 75.9%; H, 8.9%. Found: C, 76.0%; H, 8.8%.

This compound has anabolic activity.

EXAMPLE 221 dl-3-(13-Ethyl-17β-hydroxy-3-oxogon-4-en-17α-yl)propionicacid, γ-lactone

Add 13-ethyl-17α-ethynyl-3-methoxygona-1,3,5(10)-trien-17β-ol (20 g) intetrahydrofuran with stirring to refluxing 3M ethereal methylmagnesiumbromide (240 ml)-tetrahydrofuran (300 ml). Pass gaseous carbon dioxideinto the cooled mixture for 22 hours. Add the mixture to crushed ice,acidify with dilute sulfuric acid, remove most of the tetrahydrofuranunder reduced pressure and extract the mixture with ether. Extract theethereal solution with aqueous sodium carbonate and acidify theextracts. Filter off the crudedl-3-(13-ethyl-17β-hydroxy-3-methoxygona-1,3,5(10)-trien-17α-yl)prop-2-ynoicacid, m.p. 172°-173°. Recrystallize an aliquot from methanol to obtainpure substance, m.p. 173°-174° (gas evolution).

C₂₃ H₂₈ O₄ Calculated: C, 75.0%; H, 7.7% Found: C, 74.9%; H, 7.4%

Hydrogenate the foregoing acid (3.7 g) in ethanol (100 ml) over 10%palladized charcoal (1 g) until hydrogen uptake ceases. Recrystallizethe product from ethyl acetate-hexane to obtaindl-3-(13-ethyl-17β-hydroxy-3-methoxygona-1,3,5(10)-trien-17α-yl)propionicacid, γ-lactone, m.p. 174°-175°, infrared absorption peak at 5.67 μ.

C₂₃ H₃₀ O₃ Calculated: C, 77.9%; H, 8.5%. Found: C, 77.6%; H, 8.4%.

Reflux the foregoing lactone with triethylamine (180 ml) and sodiumhydroxide (1.0 g) in water (33 ml) overnight. Evaporate the mixture todryness and treat residue with a solution of tert-butyl alcohol (100ml), 1-methoxy-2-propanol (200 ml) and liquid ammonia (600 ml). Addlithium (5.0 g) and after 40 minutes add ammonium chloride (40 g)followed by water. Acidify with cold hydrochloric acid (18%) in thepresence of ice and filter off the precipitate. Add the dried material(2.4 g) to methanol (110 ml), concentrated hydrochloric acid (5 ml) andwater (5 ml) and stir for one hour. Dilute with water and filter theprecipitate. Recrystallize the dried material from ethyl acetate-hexaneto obtain 1.1 g. of the title product; m.p. 214°-215°; ultravioletabsorption peak at 240 mμ (ε17,100).

C₂₂ H₃₀ O₃ Calculated: C, 77.15%; H, 8.83% Found: C, 77.20%; H, 8.61%

EXAMPLE 222 dl-13-Ethyl-17β-hydroxy-17-(1-hydroxyethyl)gon-4-en-3-one

Reduce dl-13-ethyl-17α-acetyl-17-hydroxy-3-methoxygona-1,3,5(10)-triene,acetate (1.0 g) in lithium aluminum hydride and ether to produce a gum,dl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-1,3,5(10)-triene(0.9 g); infrared absorption peak very strong at 2.9 μ(OH band). Reducedl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-1,3,5(10)-triene(0.9 g) with tetrahydrofuran (60 ml), liquid ammonia (150 ml), lithium(700 mg) and absolute ethanol, and filter to obtain a crystalline solid,dl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-2,5(10)-diene(0.70 g), m.p. 152°-161°; ultraviolet analysis indicating no remainingaromatic system, infrared maxima at 3.0 μ, 5.9 μ, 6.0 μ.

Hydrolyzedl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-2,5(10)-diene(0.70 g) in hydrochloric acid-methanol-water. Recrystallize from ethylacetate to obtain the title compound (0.36 g), m.p. 159°-164°;ultraviolet absorption peak at 240 mμ (ε15,230), infrared absorptionpeaks at 3.0 μ (strong), 6.05 μ.

C₂₁ H₃₂ O₃ Calculated: C, 75.85%; H, 9.70%. Found: C, 76.12%; H, 9.78%.

This compound has progestational activity.

EXAMPLE 223 dl-17-Hydroxy-17α-ethynylestr-4-en-3-one, acetate

Treat dl-17-hydroxy-17α-ethynylestr-4-en-3-one (1 g) with aceticanhydride (10 ml) and toluene-p-sulfonic acid (0.1 g) and heat at 90°for 1 hour. Pour the cooled solution into water, neutralize with sodiumbicarbonate and extract with ether. Wash, dry and evaporate to obtaindl-17-ethynylestra-3,5-diene-3,17β-diol, diacetate; infrared absorptionmaxima at 3μ, 5.7μ, 5.75μ.

Hydrolyze dl-17-ethynylestra-3,5-diene-3,17β-diol, diacetate (0.4 g) inmethanol (60 ml) and tetrahydrofuran (10 ml) with 2% methanolicpotassium hydroxide at 0° for 1 hour. Pour into water, neutralize withdilute hydrochloric acid and extract with ether. Wash, dry and evaporatethe ethereal solution and chromatograph the product on ethyl acetatewashed alumina. Recrystallize the product from ether-light petroleumether to obtain the title compound (0.3 g), m.p. 153°-155°; ultravioletabsorption peak at 240 mμ (ε16,400); infrared absorption maxima at 3.1μ, 3.45 μ, 5.22 μ, 6.0 μ.

C₂₂ H₂₈ O₂ Calculated: C, 77.65%; H, 8.29%. Found: C, 78.1%; H, 8.47%.

This compound has progestational activity.

EXAMPLE 224 dl-17α-(3-Diethylamino-1-propynyl)-13-ethylgon-4-en-17-ol

Stir a suspension of 1.1 g. of dl-17α-ethynyl-13-ethylgon-4-en-17-ol, 12ml. of dioxane, 0.6 ml. of water, 0.6 ml. of formaldehyde (40% inwater), 0.5 ml. of diethylaniline, 0.4 ml. of acetic acid, and 20 mg. ofcuprous chloride for 22 hours at 60°. Pour into ice, basify with sodiumhydroxide and extract with ether. Mix the residue with a solution ofaqueous hydrochloric acid and acetic acid and extract with ether.Basifly the aqueous layer with aqueous potassium hydroxide and filteroff the product. Recrystallize from 35 ml. of methanol to obtain 900 mg.of the desired product; m.p. 149°-150°.

C₂₆ H₄₁ NO Calculated: C, 81.40%; H, 10.77%; N, 3.65%. Found: C, 81.44%;H, 10.81%; N, 3.63%. This compound has antiinflammatory activity.

EXAMPLE 225 dl-13-Ethyl-17-ethynylgon-4-en-3,17β-diol-3-acetate

Add sodium borohydride (1.0 g) to13-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one (1.0 g) in ethanol (100ml) and allow the mixture to stand for 2 hours. Decompose excess reagentwith acetic acid and remove most of the solvent under reduced pressure.Dissolve the product in ether and water, and wash, dry and evaporate theethereal solution. Dissolve the residue in pyridine (5 ml) and aceticanhydride (5 ml) and after 3 hours remove the solvents under vacuum. Addether, wash, dry and evaporate the ethereal solution and recrystallizethe residue from ethyl acetate-methanol to obtain the title compound(0.42 g), m.p. 168°-170°.

C₂₃ H₃₂ O₃ Calculated: C, 77.49%; H, 9.05%. Found: C, 77.12%; H, 9.35%.

This compound has progestational activity.

EXAMPLE 226 dl-13-Ethyl-17β-(tetrahydropyran-2-yloxy)gon-4-en-3-one

Add with swirling a solution of p-toluenesulfonic acid (14 mg) inbenzene (0.8 mole) to dl-17β-hydroxy-13-ethylgon-4-en-3-one (450 mg) in2,3-dihydropyran (3 ml). After 2 hours, neutralize the reaction mixturewith methanolic sodium hydroxide. Add water, together with somemethanol, scratch the mixture and allow it to stand at 0° for about 70hours. Filter to obtain the title compound (100 mg), m.p. 148°-152°;infrared absorption peaks at 6.0 μ, 6.2 μ, 9.02 μ, 9.42 μ, 9.68 μ, 9.85μ, 10.25 μ (no hydroxyl band).

C₂₄ H₃₆ O₃ Calculated: C, 77.31%; H, 9.74%. Found: C, 77.15%; H, 9.52%.

This compound has anabolic activity.

EXAMPLE 227 dl-13-Ethyl-17α-ethynyl-17-hydroxy-6α-methylgon-4-en-3-one

Reflux dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (5.5 g) intoluene (200 cc) and cyclohexanone (70 cc) with aluminum isopropoxide(4.0 g) for 2.5 hours. Add water and anhydrous sodium sulfate, filterand isolate the crude product. Triturate with ice cold methanol toobtain dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17-one (3.6 g),m.p. 118°-125°, λmax. KBr 5.78 μ, 5.90 μ, 6.0 μ. An analytical samplerecrystallized from methanol has m.p. 163°-166°.

Stir dl-13-ethyl-3-methoxy-6-methylgona-2,5(10) -dien-17-one (3.6 g) indimethylacetamide (35 cc) in a stream of acetylene for one-half hour.Add lithium acetylide-ethylenediamine (2.7 g) and stir for 4 hours. Pourinto ice water, extract with ether and isolate thedl-13-ethyl-3-methoxy-17α-ethynyl-17β-hydroxy-6-methylgona-2,5(10)-dieneas a gum (3.5 g), λmax. NaCl 2.90 μ, 3.05 μ, 5.90 μ, 6.03 μ.

Stirdl-13-ethyl-3-methoxy-17α-ethynyl-17-hydroxy-6-methylgona-2,5(10)-diene(3.5 g) in methanol (90 cc) containing hydrochloric acid (60 cc) andwater (4.0 ml) under nitrogen for 1 hour. Isolate the crude product,chromatograph on Florex (150 g) and recrystallize from ethylacetate-hexane to obtain the title compound (0.60 g), m.p. 148°-151°,λmax. CHCl₃ 2.55 μ, 3.05 μ, 6.01 μ; λmax. EtOH 240 mμ (ε15,100).

C₂₂ H₃₀ O₂ Calculated: C, 80.92%; H, 9.26%. Found: C, 81.01%; H, 9.56%.

This compound has progestational activity.

EXAMPLE 228 13-Ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one,2'-tetrahydropyranyl ether

Keep 13-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one (0.5 g) indihydropyran (5 ml)-benzene (0.8 ml) containing toluene-p-sulfonic acid(14 mg. of the hydrate) over night. Add ether and aqueous sodiumbicarbonate. Evaporate the washed and dried ether solution. Purify theproduct by chromatography on alumina and recrystallize from hexane toobtain the title substance (0.22 g), m.p. 145°-150°.

C₂₆ H₃₀ O₃ Calculated: C, 78.4%; H, 9.15%. Found: C, 78.7%; H, 9.0%.

This compound has progestational activity.

EXAMPLE 229 17α-Chloroethynyl-13-ethyl-17β-hydroxygon-4-en-3-one,2'-tetrahydropyranyl ether

Keep 17α-chloroethynyl-13-ethyl-17β-hydroxygon-4-en-3-one (0.5 g) in2,3-dihydropyran (5 ml)-benzene (0.8 ml) containing toluene-p-sulfonicacid (14 mg of the hydrate) over night, then add ether and aqueoussodium bicarbonate. Purify the product by recrystallization from hexaneto obtain the title substance, m.p. 125°-131°.

C₂₆ H₃₅ O₃ Cl Calculated: C, 72.45%; H, 8.2%; Cl, 8.2%. Found: C, 72.4%;H, 8.1%; Cl, 8.2%.

This compound has progestational activity.

EXAMPLE 230 13,17α-Diethyl-17β-hydroxygon-4-en-3-one,2'-tetrahydropyranyl ether

Keep 13,17α-diethyl-17β-hydroxygon-4-en-3-one (0.5 g) in2,3-dihydropyran (5 ml)-benzene (0.8 ml) containing toluene-p-sulfonicacid overnight, then add ether and aqueous sodium bicarbonate. Purifythe product by chromatography on alumina to obtain the title substance.

This compound has anabolic activity.

EXAMPLE 231 dl-13-Ethyl-17β-hydroxy-6α-methylgon-4-en-3-one

Reflux 2-(6-m-methoxyphenyl)-3-oxoheptyl-2-ethylcyclopentane-1,3-dione(53.3 g) in benzene (600 cc) with p-toluenesulfonic acid monohydrate (15g) using a water separator. Wash, dry and evaporate the benzene solutionand distil the residual gum at .003 mm./180°-200°C. Obtain thedl-3-methoxy-6-methyl-13-ethylgona-1,3,5(10),8,14-pentaen-17-one as anorange gum (38.0 g), λ max. EtOH 311 mμ (ε27,200).

Reflux 2-(6-m-methoxyphenyl)-3-oxoheptyl-2-ethylcyclopentane-1,3-dione(39.7 g) in benzene (500 cc) with p-toluenesulfonic acid monohydrate(11.0 g) using a water separator. After removal of two moles of water,add ethylene glycol (50 cc) and reflux the solution 16 hours. Wash, dryand evaporate the benzene solution and dissolve the residue in hexane.Filter the solution several times through Florex, remove the solvent andrecrystallize the residue from ethanol to obtain thedl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10),8,14-pentaene (16.8 g), m.p. 116°-119°. Recrystallize a small portion toobtain an analytical sample, m.p. 120°-122°C, λmax. EtOH 312 mμ(ε31,000).

Monohydrogenatedl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10),8,14-pentaene (15.3 g) in benzene (300 cc) in the presence of 2%Pd/CaCO₃ (5.0 g). Filter, remove the benzene under reduced pressure andrecrystallize from 95% ethanol (110 cc) to yield thedl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10),8-tetraene(11.0 g), m.p. 122°-124°, diamond shaped plates, λmax. EtOH 280 mμ(ε15,140).

Adddl-3-methoxy-6-methyl-17,17-ethylenedioxy-13-ethylgona-1,3,5(10),8-tetraene(11.0 g) in tetrahydrofuran (160 cc) to liquid ammonia (600 cc)containing tetrahydrofuran (170 cc) and aniline (30 cc). Add lithium(0.6 g) in small portions and stir for 2 hours. Add solid ammoniumchloride followed by water and extract with ether. Isolate the productwhich crystallizes on scratching, λmax. EtOH 280 mμ (ε1,975). To obtainan analytical sample recrystallize from isopropanol to obtain thepurified title compound, m.p. 130°-134°C.

Suspenddl-3-methoxy-17,17-ethylenedioxy-6-methyl-13-ethylgona-1,3,5(10)-triene(9.0 g) in methanol (200 cc) and concentrated hydrochloric acid (5.0 cc)and heat on the steam bath for 15 minutes. Remove the solvent undervacuum, partition the residue between ether and aqueous sodiumbicarbonate and isolate the product. Recrystallize from methanol toobtain the dl-3-methoxy-6-methyl-13-ethylgona-1,3,5(10)-trien-17-one(7.29 gl, m.p. 115°-123°C. Recrystallize a small portion to obtain ananalytical sample, m.p. 123°-127°C, λmax. EtOH 280 mμ, λ max. KBr 5.75μ.

C₂₁ H₂₈ O₂ Calculated: C, 80.73%; H, 9.03%. Found: C, 80.43%; H, 8.96%.

Dissolve dl-3-methoxy-6-methyl- 13-ethylgona-1,3,5(10)-trien-17-one (7.0g) in methanol (300 cc) and treat with sodium borohydride (3.0 g). Afterspontaneous reflux ceases, make acid with 50% aqueous acetic acid (20cc). Pour into brine, extract with acid and isolate thedl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-1,3,5(10)-triene (6.8 g),m.p. 158°-160°C, λmax. KBr 3.05, 6.45 μ.

C₂₁ H₃₀ O₂ Calculated: C, 80.21%; H, 9.61%. Found: C, 80.8%; H, 9.40%.

Add dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-1,3,5(10)-triene(6.80 g) in tetrahydrofuran (200 cc) to liquid ammonia (800 cc)containing tetrahydrofuran (250 cc). Add lithium metal (3.5 g)portionwise and stir the solution for 1.75 hours. Discharge the bluecolor by dropwise addition of absolute ethanol over 0.25 hours followedby water (2,000 cc). Filter, wash and dry to obtain thedl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (6.5 g),m.p. 176°-182°, λ max. KBr 3.05 μ, 5.90 μ, 6.0 μ, no absorption in theultraviolet above 220 mμ.

Stir dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (1.0g) in methanol (54 cc) containing concentrated hydrochloric acid (3.6cc) and water (2.4 cc) under nitrogen for 1.5 hours. Pour into brine,extract with ether and isolate the crude product. Chromatograph on GradeI neutral alumina (50 g) and recrystallize from ether-hexane to obtainthe title compound (0.30 g), m.p. 127°-130°, λ max. KBr 2.98 μ, 6.03 μ;λmax. EtOH 240 mμ (ε16,500).

C₂₀ H₃₀ O₂ Calculated: C, 79.42%; H, 10.00%. Found: C, 79.57%; H, 9.87%.

This compound has progestational activity.

EXAMPLE 232 dl-13-Ethyl-17-ethynylgon-4-en-3,17β-diol, 3-propionate

Add sodium borohydride (0.8 g) to13-ethyl-17-ethynyl-17β-hydroxygon-4-en-3-one (1.7 g) in ethanol (100ml) and allow the mixture to stand for 15 hours. Dilute the mixture withwater and extract with ether. Wash, dry and evaporate the etherealsolution and dissolve the residue in pyridine (5 ml) and propionicanhydride (5 ml). After 2 hours add ice and water and extract themixture with ether. Wash the ethereal extract with water, 10% aqueoussodium hydroxide, water, 10% hydrochloric acid, and brine and dry.Evaporate the solvent and recrystallize the product from ethyl acetateto obtain the title compound (0.5 g), m.p. 153°-156°.

C₂₄ H₃₄ O₃ Calculated: C, 77.8%; H, 9.25%. Found: C, 77.63%; H, 9.16%.

This compound has progestational activity.

EXAMPLE 233 dl-13-Ethyl-17α-ethynyl-17-hydroxy-6α-methylgon-4-en-3-oneand dl-13,17α-Diethyl-17-hydroxy-6α-methylgon-4-en-3-one

Dissolve2-ethyl-2-(6-m-methoxyphenyl-6-methyl-3-oxohexyl)-1,3-cyclopentanedione(39.7 g) in benzene (500 ml) and reflux with p-toluenesulfonic acid inwater (11.0 g). Remove 2 moles of water, add ethyleneglycol (50 ml) andreflux the solution overnight (16 hours). After working up by the usualprocedure, filter repeatedly through Florex in hexane. Recrystallizefrom ethanol to obtaindl-13β-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5-(10),8,14-pentaene(16.8 g), m.p. 120°-122°; ultraviolet absorption peak at 312 mμ, noinfrared absorption in the ketone region.

Hydrogenatedl-13β-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene(15.3 g) in benzene (300 ml) with 2% palladized strontium carbonate (5.0g). The uptake of 1,040 ml. will require 10 minutes. Work up in theusual manner, then recrystallize from 95% ethanol (110 ml) to obtaindl-13β-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8-tetraene(11.0 g. of diamond-shaped plates; 71.8% yield), m.p. 122°-124°;ultraviolet absorption peak at 280 mμ (ε15,140).

Adddl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8-tetraene(11.0 g) in tetrahydrofuran (160 ml) to liquid ammonia (600 ml)containing tetrahydrofuran (170 ml) and aniline (30 ml). Then addlithium (0.6 g) in small portions and stir for 2 hours. Work up in theusual way to obtaindl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5-(10)-trieneas a gum (9.5 g) that will crystallize on scratching. Recrystallize fromisopronanol to obtain a product with m.p. 130°-134°; ultavioletabsorption peak at 280 mμ (ε1,976), no infrared absorption in the ketoneregion.

Suspenddl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10)-triene(9.0 g) in methanol (200 ml) and concentrated hydrochloric acid (5 ml).Heat the mixture on a steam bath for 15 minutes. Remove the solventunder vacuum and partition the residue between ether and aqueous sodiumbicarbonate. Remove the organic solvents and dry to obtain a gum.Recrystallize from methanol to obtaindl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.29 g), m.p.115°-123°. Recrystallize from methanol to obtain an analytical samplewith m.p. 123°-127°; ultraviolet absorption peak at 280 mμ (ε2,190),infrared maximum (potassium bromide) at 5.75 μ.

C₂₁ H₂₈ O₂ Calculated: C, 80.73%; H, 9.03%. Found: C, 80.43%; H, 8.96%.

Dissolve dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.0g) in methanol (300 ml) and treat with sodium borohydride (3.0 g). Afterspontaneous reflux ceases, acidify the reaction mixture with 50% aceticacid (20 ml). Work up by the usual procedures to obtaindl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10) -trien-17β-ol (6.8 g), m.p.158°-160°; infrared absorption peaks (potassium bromide) at 3.05 μ, 6.45μ.

C₂₁ H₃₀ O₂ Calculated: C, 80.21%; H, 9.61%. Found: C, 80.13%; H, 9.40%.

Add dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17β-ol (6.80 g)in tetrahydrofuran (200 ml) to ammonia (800 ml) containingtetrahydrofuran (250 ml). Add lithium (3.5 g) and stir the solution for1.75 hours. Discharge the blue color by dropwise addition of ethanolover a period of 0.25 hour. Add water. Filter and dry the product,dl-13, -ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (6.5 g), m.p.176°-182°; infrared absorption peaks (potassium bromide) at 3.05 μ, 5.90μ, 6.0 μ, no selective ultraviolet absorption above 220 mμ

Dissolve dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (5.5 g)in toluene (200 ml) containing cyclohexanone (70 ml) and treat withaluminum isopropoxide (4.0 g) in toluene (50 ml). Reflux under nitrogenfor 2.5 hours, then add water (10 ml) followed by anhydrous sodiumsulfate (5 g). Stir the suspension for 0.5 hour, filter, and wash thefilter cake with benzene. Remove the solvents and concentrate theresidue at 100° under vacuum (.02 mm). Triturate the crystalline residuewith ice-cold methanol to obtaindl-13β-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g), m.p.118°-125°; infrared absorption peaks (potassium bromide) at 5.78 μ, 5.90μ, 6.00 μ, no selective ultraviolet absorption above 220 mμ.

Dissolve dl-13-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g)in dimethylacetamide (35 ml) and stir in a stream of acteylene for 0.5hour. Add solid lithium acetylide-ethylenediamine (2.7 g) and stir thesolution for 4 hours. Pour the reaction mixture onto ice, extract withether, wash the ether layer with water, dry, and evaporate to obtaindl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene(3.5 g) as a gum; infrared absorption peaks (sodium chloride) at 2.90 μ,3.05 μ, 5.90 μ, 6.03 μ.

Dissolvedl-13-ethyl-3-methoxy-6-methyl-17α-ethynyl-17-hydroxygona-2,5(10)-diene(3.5 g) in methanol (90 ml) containing concentrated hydrochloric acid(6.0 ml) and water (4.0 ml). Stir the solution under nitrogen for 1hour. Work up in the usual fashion. Chromatograph on Florex (150 g),then recrystallize from ether-hexane to obtaindl-13-ethyl-17α-ethynyl-17-hydroxy-6α-methylgon-4-en-3-one (0.60 g),m.p. 148°-151°; ultraviolet absorption peak at 240 mμ (ε15,300),infrared maxima (chloroform) at 2.55 μ, 3.05 μ, 6.01 μ.

C₂₂ H₃₀ O₂ Calculated: C, 80.92%; H, 9.25%. Found: C, 81.01%; H, 9.56%.

This compound has progestational activity.

Hydrogenate dl-13-ethyl-17α-ethynyl-17-hydroxy-6α-methylgon-4-en-3-one(0.15 g) in benzene (20 ml) with 2% palladized strontium carbonate (25mg). Recrystallize from ether to obtaindl-13,17α-diethyl-17-hydroxy-6β-methylgon-4-en-3-one (0.03 g); infraredabsorption peaks at 2.95 μ, 6.04 μ, 6.20 μ.

This compound has anabolic activity.

EXAMPLE 234 dl-13-Ethyl-17aα -chloroethynyl-17aβ-hydroxy-D-homogon-4-en-3-one

Dissolve dl-13-ethyl-3-methoxy-D-homogona-2,5(10)-dien- 17aβ-ol (20.5 g)in toluene (350 cc) and cyclohexanone (100 cc) and azeotrope undernitrogen to remove water. Add aluminum isopropoxide (16.0 g) in toluene(50 cc) and reflux for 2 hours. Cool, add water (20 cc), stir for 15minutes and add anhydrous sodium sulfate (40 g). Filter and isolate thecrude product by concentration under vacuum. Triturate with boilingmethanol (200 cc), filter and dry to obtaindl-13-ethyl-3-methoxy-D-homogona-2,5(10)-dien-17a-one (18.0 g), m.p.135°-140°, λmax. KBr 5.87 μ, 6.0 μ.

Dilute methyl lithium (94.6 g, 0.218 M) in ether with ether (200 cc) andcool to 0°. Add cis-dichloroethylene (11.0 g. 0.109 M) over one hour.Add dl-13-ethyl-3-methoxy-D-homogona-2,5(10)-dien-17a-one (12.0 g)suspended in ether (250 cc). Stir at room temperature for 1 hour, coolin an ice bath and add saturated aqueous ammonium chloride (250 cc)dropwise. Separate, wash, dry and evaporate the ether layer andtriturate the crystalline residue with boiling methanol (100 cc).Filtrate gives dl-13-ethyl-17aα-chloroethynyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ -ol (13.0 g), m.p.120°-126°C. λmax. KBr 3.0 μ, 4.54 μ, 5.90 μ, 5.99 μ.

Suspend dl-13-ethyl-17aα-chloroethynyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ -ol (13.0 g) inmethanol (180 cc), water (8.0 cc) and concentrated hydrochloric acid(12.0 cc), and stir under nitrogen. Add tetrahydrofuran (15 cc) anddioxane (15 cc) to effect solution. Pour into brine, extract with etherand isolate the crude product. Recrystallize from ethyl acetate (100 cc)and hexane (70 cc) to obtain the title compound (7.4 g), m.p.204°-206°C, λmax. KBr 2.90, 4.52, 6.0 μ; λmax. EtOH 240 mμ (ε16,820)

C₂₂ H₂₉ O₂ Cl Calculated: C, 73.21%; H, 8.10%; Cl, 9.82%. Found: C,73.48%; H, 8.10%; Cl, 9.6%.

This compound has progestational activity.

EXAMPLE 235 dl-13,17α-Diethylgon-4-en-3,17-diol, 3-propionate

Treat dl-13,17α-diethylgon-4-en-3,17-diol (1.0 g) in pyridine (25 ml)with propionic anhydride (2 ml) and allow to stand at room temperaturefor 14 hours. Evaporate the solvents under reduced pressure to give thetitle compound as a glass (1.18 g), infrared absorption peaks at 2.93 μ,5.80 μ and 6.0 μ.

C₂₄ H₃₈ O₃ Calculated: C, 76.96%; 10.23%. Found: C, 76.40%; 10.70%.

This compound has anabolic activity.

EXAMPLE 236 dl-13-Ethyl-17aβ -hydroxy-D-homogon-4-en-3-one

Add dl-13-ethyl-D-homo-3-methoxygona-1,3,5(10)-trien-17aβ -ol (24.4 g)in tetrahydrofuran (200 cc) to liquid ammonia (1,000 cc) containingtetrahydrofuran (300 cc). Add lithium metal (7.0 g) portionwise and stirfor 1.5 hours. Add absolute ethanol dropwise until the blue color isdischarged, followed by water. Boil the precipitated solid with methanol(200 cc) and chill. Filter and dry thedl-13-ethyl-D-homo-3-methoxygona-2,5(10)-dien-17 -aβ-ol (20.5 g), m.p.141°-143°, λ max. KBr 3.05, 5.88, 5.97 μ.

Hydrolyze dl-13-ethyl-3-methoxy-D-homogona-2,5(10)-dien-17aβ-ol (1.30 g)in methanol (90 cc), concentrated hydrochloric acid (6.0 cc) and water(4.0 cc). Isolate the product and recrystallize from ethyl acetate toobtain the title compound (0.55 g), m.p. 144°-146°, λ max. KBr 2.95,6.04 μ; λ max. EtOH 240 mμ (ε16,360).

C₂₀ H₃₀ O₂ Calculated: C, 79.43%; H, 10.00%. Found: C, 79.20%; H, 9.93%.

This compound has anabolic and progestational activities.

EXAMPLE 237 dl-17aβ -HYdroxy-13-propyl-D-homogon-4-en-3-one,3-phenylpropionate

Add phenylpropionyl chloride (0.90 g) in benzene (5.0 cc) to a solutionof dl-17aβ -hydroxy-13-propyl-D-homogon-4-en-3-one (0.80 g) in pyridine(5.0 cc), chilled to -15°C. Allow the reaction mixture to stand at -10°Cfor 16 hours, then at room temperature for 1 hour. Pour into ice water,extract with ether and isolate the crude product. Recrystallize fromethyl acetate-hexane to obtain the title compound (0.45 g), m.p.166°-169°C, λmax. KBr 5.78, 5.98 μ; λmax. EtOH 240 mμ (ε16,900).

C₃₀ H₄₀ O₃ Calculated: C, 80.31%; H, 8.99%. Found: C, 79.98%; H, 8.64%.

EXAMPLE 238 dl-17aβ -Hydroxy-13-propyl-D-homogon-4-en-3-one, decanoate

Add decanoyl chloride (0.90 g) in benzene (5.0 cc) todl-17αβ-hydroxy-13-propyl-D-homogon-4-en-3-one (0.80 g) in pyridine (5.0cc), chilled to 15°C. Allow the reaction mixture to stand at -10° for 16hours, then at room temperature for 1 hour. Pour into ice water, extractwith ether and isolate the crude product. Recrystallize from hexane toobtain the title compound (0.375 g), m.p. 55°-58°C, λmax. KBr 5.78, 5.98μ; λmax. EtOH 240 mμ (ε15,250).

C₃₁ H₅₀ O₃ Calculated: C, 79.0%; H, 10.70%, Found: C, 78.95%; H, 10.60%.

EXAMPLE 239 dl-13β-Ethyl-17β-hydroxy-7-methylgon-4-en-3-one

Reflux dl-13-ethyl-17β-hydroxygon-4-en-3-one (3.0 g) with aceticanhydride (45 cc), acetyl chloride (24 cc) and pyridine (2.4 cc) for 3hours. Take to dryness under reduced pressure and partition the residuebetween benzene-ether and water. Triturate the crude product with hotether to obtain dl-3,17-diacetoxy-13-ethylgona-3,5-diene (3.125 g), m.p.148°-156°; λmax. KBr 5.68, 5.78, 6.0, 6.11 μ; λmax. EtOH 238 mμ(ε19,500).

Add dl-13-ethyl-3,17-dihydroxygona-3,5-diene, diacetate (1.0 g)dissolved in acetone (20 cc) to a solution of acetone (86 cc), pyridine(.59 ml), sodium acetate (2.72 cc), water (27.2 cc) and acetic acid(2.72 cc). Chill to 0° and add N-bromosuccinimide (0.5 g). Stir forthree hours at a temperature between +5° and -5°. Pour into ice-coldbrine (800 cc) and extract with ether. Wash and dry the ether layer andconcentrate, deeping the temperature below +15°. Add calcium carbonate(3.0 g) and dimethylformamide (70 cc) and distil off residual ether.Reflux one hour, cool and filter; wash the cake with ether. Pour thefiltrate into brine and extract with ether. Recrystallize from ethylacetate-hexane to obtain dl-13-ethyl-17β-acetoxygona-4,6-dien-3-one(0.475 g), m.p. 163°- 177°, λmax. KBr 5.77, 6.0 μ; λmax. EtOH 283 mμ(ε24,370).

C₂₁ H₂₈ O₃ Calculated: C, 76.80%; H, 8.59%, Found: C, 76.51%; H, 8.58%.

Add dl-13-ethyl-17β-acetoxygona-4,6-dien-3-one (2.0 g) intetrahydrofuran (30 cc) to tetrahydrofuran (20 cc) containing 3 molesmethyl magnesium bromide (16 cc) and cuprous chloride (299 mg) at 0°.Stir for 20 minutes and pour into ice-cold brine saturated with hydrogenchloride. Extract with ether and chromatograph on Grade 2.5 neutralalumina. To obtain the title compound, recrystallize from ethylacetate-hexane (0.56 g), m.p. 152°-154°; λmax. KBr 2.98, 6.02 μ; λmax.EtOH 242 mμ (ε16,730).

C₂₀ H₃₀ O₂ Calculated: C, 79.43%; H, 10.00%. Found: C, 79.11%; H, 9.92%.

This compound has antiestrogenic activity.

EXAMPLE 240 dl-13,17α-Diethyl-17-hydroxygon-4-en-3-one, acetate

Reflux dl-13,17α-diethyl-17-hydroxygon-4-en-3-one (3.0 g) with aceticanhydride (48 cc), acetyl chloride (24 cc) and pyridine (2.4 cc) for 2hours. Take the reaction mixture to dryness under reduced pressure andpartition the residue between benzene-ether and water. Wash, dry andevaporate the organic layer to obtain the crudedl-13,17α-diethyl-3,17-dihydroxygona-3,5-diene, diacetate. To obtain ananalytical sample, triturate the crystalline crude product with ether,filter and wash with hexane, m.p. 122°-125°C; λmax. KBr 5.71, 5.78, 6.0μ; λmax. EtOH 238 mμ (ε18,200).

C₂₅ H₃₆ O₄ Calculated: C, 74.96%; H, 9.06%. Found : C, 74.64%; H, 9.10%.

Dissolve dl-13,17α-diethyl-3,17-dihydroxygona-3,5-diene, diacetate (3.0g) in tetrahydrofuran (70 cc) and methanol (70 cc), and chill thesolution to 0°C. Add ice-cold 2% potassium in methanol (200 cc) and stirthe solution under nitrogen for 1 hour. Pour into brine, make acid with10% aqueous hydrochloric acid and extract with ether. Wash, dry andevaporate the organic layer and triturate the crystalline residue withice-cold ether to obtain the title compound (1.45 g), m.p. 121°-123°C;λmax. KBr 5.80, 5.99 μ: λmax. EtOH 240 mμ (ε17,925).

C₂₃ H₃₄ O₃ Calculated: C, 77.05%; H, 9.56%. Found: C, 76.60%; H, 9.81%.

This compound has antiestrogenic activity.

EXAMPLE 241 dl-13-Ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one, acetate

Reflux dl-13-ethyl-17α-ethynyl-17β-hydroxygon-4-en-3-one (1.0 g) for11/2 hours with acetic anhydride (16 cc), acetyl chloride (8.0 cc) andpyridine (0.8 cc). Remove the liquids under reduced pressure andpartition the dry crystalline residue between benzene-ether and water.Wash the organic solvents under reduced pressure and triturate theresidue with ice-cold ether to providedl-13-ethyl-17α-ethynyl-3,17-dihydroxygona-3,5-diene, diacetate (0.725g), m.p. 144°-150°C; λmax. KBr 3.09, 5.67, 5.77μ; λmax. EtOH 236 mμ(ε19,300).

C₂₅ H₃₂ O₄ Calculated: C, 75.72%; H, 8.11%. Found: C, 75.28%; H, 7.86%.

Dissolve dl-13-ethyl-17α-ethynyl-3,17-dihydroxygona-3,5-diene, diacetate(0.34 g) in methanol (60 cc) and tetrahydrofuran (10 cc) and chill to0°C. Add 2% potassium in methanol (20 cc) and stir the solution undernitrogen for one hour. Pour into brine, make acid with 10% aqueoushydrochloric acid and extract with ether. Wash the ether with 5% sodiumbicarbonate, water and brine. Dry the organic layer and remove thesolvent under reduced pressure. Recrystallize the residue from a smallamount of ether to provide the title compound (0.200 g), m.p. 162°-164°;λmax. KBr 3.1, 5.72, 6.02 μ; λmax. EtOH 240 mμ (ε18,185).

C₂₃ H₃₀ O₃ Calculated: C, 77.91%; H, 8.53%. Found: C, 77.46%; H, 8.29%.

This compound has progestational activity.

EXAMPLE 242 dl-13-Ethyl-17α-chloroethynyl-17-hydroxygon-4-en-3-one,acetate

Reflux dl-13-ethyl-17α-chloroethynyl-17-hydroxygon-4-en-3-one (3.0 g)for 2 hours with acetic anhydride (48 cc), acetyl chloride (24 cc) andpyridine (2.4 cc). Take the reaction mixture to dryness under reducedpressure and partition the residue between benzene-ether and water.Wash, dry and evaporate the organic phase to obtain the crudedl-13-ethyl-17α-chloroethynyl-3,17-dihydroxygona-3,5-diene, diacetate.Obtain an analytical sample by triturating this crystalline residue withcold ether and washing with hexane, m.p. 177°-180° (d) λmax. KBr 4.50,5.70, 5.75, 6.0 μ; λmax. EtOH 236 mμ (ε18,800).

C₂₅ H₃₁ O₄ Cl Calculated: C, 69.67%; H, 7.25%. Found: C, 69.93%; H,7.26%.

Dissolve dl-13-ethyl-17α-chloroethynyl-3,17-dihydroxygona-3,5-diene,diacetate (3.0 g) in tetrahydrofuran (70 cc) and methanol (70 cc) andcool to 0°-5° under nitrogen. Add 2% potassium hydroxide in methanol(200 cc) and stir for 1 hour. Pour into brine, make acid with 10%aqueous hydrochloric acid and extract with ether. Wash, dry evaporatethe ether and dissolve the residue in 10% petroleum ether-90% benzeneand filter through Grade III neutral alumina (100 g). Remove the solventand recrystallize the residue from ether-hexane to provide the titlecompound (1.275 g), m.p. 185°-187°; λmax. KBr 4.52, 5.75, 6.0 μ; λmax.EtOH 240 mμ (ε16,900).

C₂₃ H₂₉ O₃ Cl Calculated: C, 71.03%; H, 7.52%. Found: C, 71.03%; H,7.69%.

EXAMPLE 243 dl-17β-Hydroxy-17α-ethynylestr-4-en-3-one

Dissolve dl-3-methoxyestra-2,5(10)-dien-17β-ol (4 g) in cyclohexanone(40 ml) and toluene (140 ml) and add a solution of aluminum isopropoxide(4 g) in toluene (56 ml). Reflux in an atmosphere of nitrogen for twohours and cool. Add water (7.5 ml), shake, and then dry by adding sodiumsulfate (10 g). Filter and evaporate under vacuum and recrystallize theresidue from methanol to obtain dl-3-methoxyestra-2,5(10)-dien-17-one(3.5 g); m.p. 116°-118°; infrared absorption maxima at 5.76 μ, 5.9 μ,6.01 μ.

This compound has progestational activity.

Add a solution of dl-3-methoxyestra-2,5(10)-dien-17-one (3.5 g) indimethylacetamide (100 ml) to a suspension of lithium acetylide (3.7 g)in dioxane (25 ml) and dimethylacetamide (20 ml). Stir for three hours,pour on to ice water (200 g) and extract with ether. Wash, dry, andevaporate the ethereal solution and recrystallize the residue frommethanol to obtain dl-17α-ethynyl-3-methoxyestra-2,5(10)-dien-17β-ol (2g), m.p. 160°-164°; infrared absorption maxima at 2.95 μ, 3.15 μ, 5.9 μ,6.0 μ.

Dissolve dl-17α-ethynyl-3-methoxyestra-2,5(10)-dien-17β-ol (1 g) inmethanol (20 ml) containing concentrated hydrochloric acid (1.2 ml) andwater (0.8 ml) and stir for one hour. Add water (250 ml) and extractwith ether. Wash, dry and evaporate the ethereal solution andrecrystallize the residue from ethyl acetate-ether to obtain the titlecompound (0.63 g), m.p. 173°-174.5°; ultraviolet absorption peak at 240mμ (ε17,500); infrared absorption maxima at 3.05 μ, 6.05 μ.

C₂₀ H₂₆ O₂ Calculated: C, 80.49%; H, 8.76%. Found: C, 80.41%, H, 8.82%.

EXAMPLE 244 dl-17α-Ethyl-17-hydroxyestr-4-en-3-one

Add solid lithium acetylide-ethylenediamine complex (9.5 g) to3-methoxyestra-1,3,5(10),8-tetraen-17-one (10 g) in dimethylacetamide(100 ml), stir the mixture for 15 hours and then pour into ice water.Extract with ether-benzene (1:1), and wash, dry and evaporate theorganic extract. Recrystallize the residue from methanol to obtaindl-17α-ethynyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (2.8 g), m.p.133°-137°; infrared absorption peaks at 3.1 μ, 6.25 μ.

Add dl-17α-ethynyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (7 g) inbenzene (75 ml) to a suspension of prehydrogenated 2% palladised calciumcarbonate (3 g) in benzene (50 ml), and shake in an atmosphere ofhydrogen until two molecular equivalents of hydrogen (1,030 ml) havebeen absorbed. Filter the catalyst, evaporate the solvent andrecrystallize the residue twice from methanol to obtaindl-17α-ethyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (4.5 g), m.p.105°-120°; ultraviolet absorption maximum 278 mμ (ε12,000); infraredabsorption peaks at 2.95 μ, 6.25 μ.

Add dl-17α-ethyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (3 g) intetrahydrofuran (50 ml) to lithium (0.8 g) in aniline (8 ml) and liquidammonia (200 ml). Stir for 2 hours, decompose by adding ammoniumchloride and water, and extract with ether. Wash, dry and evaporate theorganic extract, and crystallize from ethyl acetatehexane to obtaindl-17α-ethyl-3-methoxyestra-1,3,5(10)-trien-17β-ol (2 g), m.p.133°-135°; ultraviolet absorption maximum at 279 mμ (ε2,120).

Add dl-17α-ethyl-3-methoxyestra-1,3,5(10)-trien-17-ol (2 g) in ether (55ml) to distilled liquid ammonia (180 ml), and add lithium (1 g) to thestirred solution. After 45 minutes add ethanol (15 ml) and ether (15 ml)dropwise followed by ammonium chloride and water. Extract with ether,wash, dry, evaporate, and recrystallize the residue from ether to obtaindl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g), m.p. 131°-134°.

Stir dl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g) withconcentrated hydrochloric acid (2.4 ml) in water (1.6 ml) and methanol(36 ml) for 2 hours. Add water, extract with ether and wash, dry andevaporate the ethereal solution. Recrystallize the product from ethylacetate-ether to obtain the title compound (0.63 g), m.p. 173°-174.5°;ultraviolet absorption maximum at 240 mμ (ε17,500).

C₂₀ H₂₆ O₂ Calculated: C, 80.5%; H, 8.7%. Found: C, 80.4%; H, 8.8%.

This compound has anabolic activity.

EXAMPLE 245 dl-13-Ethyl-17β-hydroxy-17α-(1-hydroxyethyl)gon-4-en-3-one

Reduce dl-13-ethyl-17α-acetyl-3-methoxygona-1,3,5(10)-triene (1 g) withlithium aluminum hydride in ether todl-13-ethyl-17-(1-hydroxyethyl)-3-methoxygona-1,3,5(10)-triene. Reducethis alcohol (0.9 g) with lithium (0.7 g) and ethanol in liquid ammonia(150 cc)-tetrahydrofuran (60 cc) todl-13-ethyl-17β-hydroxy-17α-(1-hydroxyethyl)-3-methoxygona-2,5(10)-diene.Hydrolyse this substance with methanolic hydrochloric acid andrecrystallize the product from ethyl acetate to obtain the titlesubstance, m.p. 159°-164°, λmax. 240 mμ (ε15,230).

C₂₁ H₃₂ O₃ Calculated: C, 75.85%; H, 9.7%. Found: C, 76.1%; H, 9.8%.

This compound has progestational activity.

EXAMPLE 246 13-Ethyl-17β-hydroxygon-4-en-3-one, 2'-tetrahydropyranylether

Add 2 drops of concentrated hydrochloric acid to13-ethyl-17β-hydroxygon-4-en-3-one (0.5 g), 2,3-dihydropyran (5 ml), andether (3 ml). Keep the mixture for 3 days at room temperature thendilute it with ether and add sodium bicarbonate. Recrystallize theproduct from hexane to obtain the title substance, m.p. 110°-140°.

C₂₄ H₃₆ O₃ Calculated: C, 77.4%; H, 9.7%. Found: C, 77.15%; H, 9.5%.

This compound has anabolic activity.

EXAMPLE 247 dl-13-Ethyl-17β-(2-hydroxyethoxy)gon-4-en-3-one, benzoate

Stir a solution of 4.0 g. ofdl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene, 300ml. of tetrahydrofuran, and 300 ml. of liquid ammonia. Add 4.0 g. oflithium and stir for 1 hour. Discolor with absolute alcohol, add waterand filter off the precipitate; infrared peaks at 2.91, 5.89, 6.00 μ.

Stir a suspension of 1.7 g. of the foregoing enol ether, 100 ml. ofmethanol, 8 ml. of conc. hydrochloric acid, and 5 ml. of water for 2hours. Dilute with water and extract the material with ether. Evaporatethe ether to obtain a gum.

Treat a solution of 1.3 g. of this crude material in 6 ml. of pyridinewith 1.3 ml. of benzoyl chloride at -10°. Keep the solution at -10° for22 hours, then pour it over ice and extract the mixture with ether.Chromatograph the product on alumina. Elute with benzene-ethyl acetateto obtain the title substance; infrared peaks at 5.80, 5.98 μ.

C₂₈ H₃₆ O₄ Calculated: C, 77.03%; H, 8.31%. Found: C, 77.44%; H, 8.59%.

This compound has anabolic activity.

EXAMPLE 248 dl-17β-Ethoxy-13-ethylgon-4-en-3-one

Reflux a suspension of 5.0 g. ofdl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol and 3.83 g. of sodiumhydride (50% in oil) for 1.5 hours in xylene (100 ml). Add 14.5 ml. ofethyl iodide and reflux for 22 hours. Acidify with 2N hydrochloric acidand extract the material with benzene. Chromatograph the residue onalumina (Grade I neutral). Elute the product with benzene-ether (1:1).Recrystallize the product from 60 ml. of methanol to obtaindl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene (2.3 g); m.p.74°-77°C.

C₂₂ H₃₂ O₂ Calculated: C, 80.44%; H, 9.83%. Found: C, 80.73%; H, 10.09%.

Add 2.0 g. of lithium to a suspension of 2.0 g. ofdl-17β-ethoxy-13-ethyl-3-methoxygona-1,3,5(10)-triene, 90 ml. of1,2-dimethoxyethane, 100 ml. of 1-methoxy-2-propanol, and 300 ml. ofammonia while stirring. Treat with 2.0 g. of ammonium chloride andwater, filter off the precipitate and add it to 80 ml. of methanol, 4ml. of water, and 5 ml. of conc. hydrochloric acid. Stir for one hourand dilute with water. Extract the product with ether and recrystallizeit successively from methanol-water and petroleum ether-ether to obtainthe title substance, m.p. 95°-97°; ultraviolet peak at 244 mμ (15,900);infrared peak at 6.0 μ.

C₂₁ H₃₂ O₂ Calculated: C, 79.70%; H, 10.19%. Found: C, 79.90%, H,10.38%.

This compound has progestational and anabolic activities.

EXAMPLE 249dl-13-Ethyl-17β-(1-hydroxy-2,2,2-trichloroethoxy)gon-4-en-3-one

Add 2.9 g. of dl-13-ethyl-17β-hydroxygon-4-en-3-one to a solution of 1.9g. of chloral hydrate in 10 ml. of benzene at 5°C. Keep the mixtureovernight at this temperature. Filter off the product and recrystallizeit successively from ethyl acetate and petroleum ether-benzene to obtainthe title substance, m.p. 175°-176°; ultraviolet peak at 240 mμ(ε17,500); infrared peaks at 3.10, 6.05, 6.20 μ.

C₂₁ H₂₉ Cl₃ O₃ Calculated: C, 57.87%; H, 6.71%; Cl, 24.41%. Found: C,57.82%; H, 6.64%; Cl, 24.2%.

This compound has anabolic and progestational activities.

EXAMPLE 250dl-13-Ethyl-17β-(1-hydroxy-2,2,2-trichloroethoxy)gon-4-en-3-one, acetate

Keep a solution of 1.5 g. of13-ethyl-17β-(1-hydroxy-2,2,2-trichloroethoxy)gon-4-en-3-one in aceticanhydride (5 ml) and pyridine (5 ml) for 3 days. Evaporate the solventafterwards and reflux the residue with methanol for a few minutes. Cooland filter off the title substance (1.2 g); m.p. 183°-183°; ultravioletpeak at 240 mμ (ε17,500).

C₂₃ H₃₁ Cl₃ O₄ Calculated: C, 57.81%; H, 6.54%; Cl, 22.26%. Found: C,57.76%; H, 6.37%; Cl, 22.2%.

This compound has anabolic and progestational activities.

EXAMPLE 251 dl-13-Ethyl-17β-propoxygon-4-en-3-one

Reflux a suspension of 5.0 g. ofdl-13-ethyl-3-methoxygona-1,3,5(10)-triene-17β-ol, 100 mg. of xylene,and 3.9 g. of sodium hydride (50% in mineral oil) for 1.5 hours. Add14.5 ml. of allyl bromide and reflux for 22 hours. Make the reactionmixture acidic with dilute hydrochloric acid and extract the organiclayer with sodium bicarbonate solution. Chromatograph the residue onalumina (Grade I neutral) in hexane and elute the product with ether toobtain dl-17β-allyloxy-13-ethyl-3-methoxygona-1,3,5(10)-triene.

Hydrogenate 3.0 g. ofdl-17β-allyloxy-13-ethyl-3-methoxygona-1,3,5(10)-triene in 100 ml. ofbenzene and 1.0 g. of 10% palladized charcoal at atmospheric pressure.Filter off the catalyst and recrystallize the residue from methanol toobtain 2.3 g. of the desired product, m.p. 83°-84°C; λmax. 279 (ε2,010).

C₂₃ H₃₄ O₂ Calculated: C, 80.65%; H, 10.01% Found: C, 80.42%; H, 9.80%

Treat a suspension of 1.5 g. ofdl-13-ethyl-3-methoxy-17β-propoxygona-1,3,5(10)-triene, 75 ml. of1,2-dimethoxyethane, 75 ml. of 1-methoxy-2-propanol, and 300 ml. ofliquid ammonia with 5.0 g. of lithium. When the reaction ends add 1.5 g.of ammonium chloride and water. Collect the precipitate ofdl-13-ethyl-3-methoxy-17β-propoxygona-2,5(10)-diene, and add it to asolution of 50 ml. of methanol, 5 ml. of conc. hydrochloric acid, and 4ml. of water. Stir for 0.5 hours. Filter off a small amount of insolublematerial. Add water to clean solution and extract with ether.Recrystallize from etherpetroleum ether to obtain the title product,m.p. 88°-89°; ultraviolet peak at 242 mμ (ε16,600); infrared peaks at6.00, 6.19μ.

C₂₂ H₃₄ O₂ Calculated: C, 79.95%; H, 10.37%. Found: C, 80.02%; H,10.20%.

This compound has anabolic activity.

EXAMPLE 252 dl-17-Chloroethynyl-13-ethylgon-4-en-3,17β-diol

Stir a solution of (5.0 g)dl-17-chloroethynyl-17β-hydroxy-13-ethylgon-4-en-3-one and 150 ml. ofabsolute alcohol (ice-bath), add 2.0 g. of sodium borohydride andcontinue to stir for three hours at room temperature. Add acetic acidand water and extract with ether. Wash the ether solution with sodiumbicarbonate solution. Evaporate the solvent to obtain 5.0 g. of thetitle product; no infrared absorption in the 6 μ region.

This compound has pituitary-blocking activity.

EXAMPLE 253 dl-17-Chloroethynyl-13-ethylgon-4-ene-3,17β-diol, 3-acetate

Treat a mixture of 2.0 g. ofdl-17-chloroethynyl-13-ethylgon-4-ene-3,17β-diol, 10 mg. of pyridinewith 15 ml. of acetic anhydride. Keep the solution overnight at roomtemperature, and then pour it into ice-water; acidify with 2 Nhydrochloric acid and extract with ether. Evaporate the ether andcrystallize residue from methanol-water to obtain 900 mg. of desiredproduct, m.p. 156°-160°; infrared peaks at 2.90, 4.54, 5.80, 6.00 μ.

C₂₃ H₃₁ O₃ Cl Calculated: Cl, 9.09%. Found; Cl, 9.01%.

This compound has progestational activity.

EXAMPLE 254 dl-17β-(2-Diethylaminoethoxy)-13-ethylgon-4-en-3-one,citrate

Stir a solution of 100 ml. of ether, 13.3 g. aluminum chloride and 15ml. of lithium aluminum hydride (1 molar solution) for 40 minutes. Add asolution of 17.1 g. ofdl-13-ethyl-17,17-ethylenedioxy-3-methoxygona-1,3,5(10)-triene in 1liter of ether and stir for 4 hours. Dilute with 2 N sulfuric acid untilclear solution results. Separate the ether layer and evaporate thesolvent. Treat residue with 20 ml. of ethanol, 5 ml. of conc.hydrochloric acid, and 10 ml. of water on steam bath for 30 minutes.Crystallize the product from ethanol to obtain 8.1 g.dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene; m.p.131°-132°.

C₂₂ H₃₂ O₃ Calculated: C, 76.70%; H, 9.36%. Found: C, 76.81%; H, 9.35%.

Stir a cooled solution of 344 mg. ofdl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene in 2ml. of pyridine (acetone-dry ice bath) and add dropwise 0.14 ml. ofmethanesulfonyl chloride. After 2 hours bring reaction mixture to roomtemperature. Mix with ice and water and a few drops of methanol toobtain a crystalline precipitate. Recrystallize this to obtaindl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene methanesulfonate from methanol (310 mg); m.p. 104°.

C₂₃ H₃₄ O₅ S Calculated: C, 65.37%; H, 8.11%; S, 7.60%. Found: C,65.62%; H, 8.22%, S, 7.85%.

Reflux a suspension of 2.3 g. of the foregoing ester with 50 ml. ofdiethylamine for 6 hours. Evaporate the solvent and treat the residuewith aqueous acetic acid. Extract the non-basic fraction with ether.Basify the acidic layer and separate the product with ether.Recrystallize from methanol-water to obtaindl-13-ethyl-17β-(2-diethylaminoethoxy)-3-methoxygona-1,3,5(10)-triene;m.p. 66°-67°.

C₂₆ H₄₁ NO₂ Calculated: C, 78.14%; H, 10.34%; N, 3.51%. Found: C,77.85%; H, 10.03%; N, 3.52%.

Add 3.0 g. of lithium to a stirred solution of 4.0 g. of17β-(2-diethylaminoethoxy)-13-ethyl-3-methoxygona-1,3,5(10)-triene, 200ml. of morpholine, 200 ml. of tetrahydrofuran, 100 ml. of1-methoxy-2-propanol, and 500 ml. of liquid ammonia. Treat with 25.0 g.of ammonium chloride and water and extract with ether to obtain 3.0 g.of dl-13-ethyl-17β-(2-diethylaminoethoxy)-3-methoxygona-2,5(10)-diene.

Add 50 ml. methanol, 5 ml. of conc. hydrochloric acid and 4 ml. of waterto the foregoing enol ether and stir for 2 hours. Add sodium hydroxidesolution (10%) and extract product with ether. Purify product bychromatography on alumina (Grade I neutral). Evaporate the methanoleluate, dissolve the residue in 100 ml. of ether and add 650 mg. ofcitric acid hydrate in 600 ml. of ether to the solution. Filterprecipitate to obtain the title product (0.9 g).

C₃₁ H₄₉ NO₉ Calculated: N, 2.42%. Found: N, 2.61%.

EXAMPLE 255 dl-13-Ethyl-17α-ethynyl-17β-hydroxy-7α-methylgon-4-en-3-one

Reflux dl-13-ethyl-17β-hydroxy-7α-methylgon-4-en-3-one (1.35 g) inbenzene (100 ml) with ethylene glycol (10 cc) and p-toluene-sulfonicacid hydrate (67 mg) for 6 hours using a water separator. Wash, dry andevaporate the solvent to obtain thedl-13-ethyl-3,3-ethylenedioxy-17β-hydroxy-7α-methylgon-5 and 5(10)-ene,as a gum, λmax. NaCl 2.90 μ.

Subject dl-13-ethyl-3,3-ethylenedioxy-17β-hydroxy-7α-methylgon-5 and5(10)-ene (1.4 g) to Oppenauer oxidation by refluxing in the presence oftoluene (50 cc), cyclohexanone (10 cc) and aluminum isopropoxide (0.80g) for 3.5 hours.

Isolate the dl-13-ethyl-3,3-ethylenedioxy-7α-methylgon-5 and5(10)-ene-17-one as a gum by addition of water (0.5 cc), sodium sulfateanhydrous (6.0 g), filtration and concentration under high vacuum, λmax.NaCl 2.9, 5.75, 5.85 μ.

Dissolve dl-13-ethyl-3,3-ethylenedioxy-7α-methylgon-5 and5(10)-en-17-one (1.3 g) in dimethylacetamide (50 cc) and stir in astream of acetylene in the presence of lithium acetylide-ethylenediamine(1.0 g) for 2 hours. Add ice, extract with ether and isolate the crudedl-13-ethyl-3,3-ethylendioxy-17α-ethynyl-17β-hydroxy-7α-methylgon-5 and5(10)-ene (0.8 g). Infrared spectral data indicate no ketone remaining.

Dissolve crudedl-13-ethyl-3,3-ethylenedioxy-17α-ethynyl-17-hydroxy-7α-methylgon-5 and5(10)-ene (0.8 g) in methanol (50 cc), hydrochloric acid (3.0 cc) andwater (2.0 cc), and stir under nitrogen for 1.5 hours. Pour into brine,extract with ether and isolate the crude product as a crystalline solid,m.p. 170°-175°. Chromatograph on Florex XXS (40.0 g) and recrystallizefrom ethyl acetate-hexane to obtain the title compound (0.550 g), m.p.182°-184°C, λmax. KBr 3.0, 3.1, 4.80, 6.09 μ.

C₂₂ H₃₀ O₂ Calculated: C, 80.92%; H, 9.26%. Found; C, 80.62%; H, 9.13%.

EXAMPLE 256 dl-13-Ethyl-17β-(2-dimethylaminoethoxy)gon-4-en-3-one

Stir a solution of 860 mg. of sodium amide in 15 ml. of benzene and add3.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-trien-17β-ol in 15 ml. ofbenzene. Heat for 2 hours at 70°-83°. Cool to room temperature and add1.58 g. of N,N-dimethylamino-2-chloroethane hydrochloride and reflux for16 hours. Pour over ice and acidify reaction mixture with 2 Nhydrochloric acid. Extract with ether and basify the aqueous layer with15% sodium hydroxide. Isolate material with ether. Evaporate the etherto obtaindl-13-ethyl-17β-(2-dimethylaminoethoxy)-3-methoxygona-1,3,5(10)-triene.

Add to a solution of 400 mg. ofdl-13-ethyl-17β-(2-dimethylaminoethoxy)-3-methoxygona-1,3,5(10)-triene,75 ml. of tetrahydrofuran, and 120 ml. of liquid ammonia, 500 mg. oflithium while stirring for 3 hours. Add absolute alcohol until thereaction mixture turns colorless. Add 6.0 g. of ammonium chloride andwater, and filter off the precipitate.

Stir this material with a solution of 12 ml. of methanol and 1 ml. of 2N hydrochloric acid for 1 hour. Basify with 10% sodium hydroxide andcollect the precipitate. Recrystallize the product from methanol-waterto obtain the title compound, m.p. 87°-88°.

C₂₃ H₃₇ O₂ N Calculated: C, 76.83%; H, 10.37%; N, 3.90%. Found: C,76.69%; H, 10.22%; N, 4.06%.

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:
 1. Atherapeutic composition having progestational activity comprising asactive ingredient a 17-aliphatic carboxylic acid ester of17α-ethynyl-18-methyl-19-nortestosterone and a pharmaceutical carrierfor said compound.
 2. A composition according to claim 1 wherein saidnortestosterone 17-ester is the 17-acetate ester.
 3. A therapeuticcomposition having progestational activity in which the activeingredient is a 17α-ethynyl-18-methyl-19-nortestosterone 17-aliphaticcarboxylic acid ester present in a progestationally effective amount. 4.A therapeutic composition according to claim 3 wherein said ester is17α-ethynyl-18-methyl-19-nortestosterone 17-acetate.
 5. A method ofproviding steroid therapy which comprises administering to a subject atherapeutic composition according to claim 3.